Abstract
Caspases are proteolytic enzymes that belong to the cysteine protease family and play a crucial role in homeostasis and programmed cell death. Caspases have been broadly classified by their known roles in apoptosis (caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9 in mammals) and in inflammation (caspase-1, caspase-4, caspase-5, and caspase-12 in humans, and caspase-1, caspase-11, and caspase-12 in mice). Caspases involved in apoptosis have been subclassified by their mechanism of action as either initiator caspases (caspase-8 and caspase-9) or executioner caspases (caspase-3, caspase-6, and caspase-7). Caspases that participate in apoptosis are inhibited by proteins known as inhibitors of apoptosis (IAPs). In addition to apoptosis, caspases play a role in necroptosis, pyroptosis, and autophagy, which are non-apoptotic cell death processes. Dysregulation of caspases features prominently in many human diseases, including cancer, autoimmunity, and neurodegenerative disorders, and increasing evidence shows that altering caspase activity can confer therapeutic benefits. This review covers the different types of caspases, their functions, and their physiological and biological activities and roles in different organisms.
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Data Availability
All data generated or analyzed during this review are included in this review article.
Abbreviations
- ALPS:
-
Autoimmune lymphoproliferative syndrome
- AD:
-
Alzheimer’s disease
- ADP-ribose:
-
Adenosine diphosphate-ribose
- ALS:
-
Amyotrophic lateral sclerosis
- APP:
-
Amyloid beta precursor protein
- ARK5:
-
AMPK-related kinase 5
- AMPK:
-
AMP-Activated protein kinase
- APP-C31:
-
Amyloid beta-protein precursor C-terminal fragments of 31
- Ac-YVAD-CMK, AIM-2:
-
Absent in melanoma 2
- AIP-1:
-
Actin-interacting protein-1
- Akt pathway:
-
Protein kinase B or serine/threonine kinase1
- BID:
-
BH3 interacting-domain death agonist
- Bap31 :
-
B-cell receptor associated protein-31
- CED:
-
Cell death abnormality protein
- CED-3:
-
Cell death abnormality protein-3
- CED-4:
-
Cell death abnormality protein-4
- CED-9:
-
Cell death abnormality protein-9
- CEDS:
-
Caspase eight deficiency stage
- CARD:
-
Caspase recruitment domain
- CD95:
-
Cluster of differentiation 95
- CPP-32:
-
Putative cysteine protease 32
- COS:
-
CV-1 in Origin with SV40 genes (African Green Monkey)
- C-JUN-N:
-
C-JUN N-terminal kinase
- Crm A:
-
Cytokine response modifier A
- CNS:
-
Central nervous system
- CCoV-II:
-
Canine coronavirus-II
- CCoV:
-
Canine coronavirus
- CP:
-
Cyclophosphamide
- CASc :
-
Cascade complex
- DNA:
-
Deoxyribonucleic acid
- dATP:
-
Deoxyadenosine triphosphate
- DICA:
-
2-(2–4-Dichlorophenoxy)-N-(2-mercapto ethyl O acetamide)
- D3 :
-
Vitamin-D/cholecalciferol
- DED:
-
Death effector domain
- EAAT2:
-
Excitatory amino acid transporter-2
- EGL-1:
-
Egg-laying defective protein-1
- ER:
-
Endoplasmic reticulum
- ERICE:
-
Evolutionary related interleukin-1β converting enzyme
- Fas:
-
Fs-7-associated surface antigen
- FasL:
-
Fas- ligand
- FICA:
-
5-Fluro-1H-indole-2 carboxylic acid(2-mercapto-ethyl-amide)
- GSDMD:
-
Gasdermin-D
- GSDMD-NT:
-
Gasdermin-D-N-terminal domain
- HCov-OC43:
-
Human coronavirus OC43
- HTT:
-
Hereditary hemorrhagic telangiectasia
- IAP:
-
Inhibitor of apoptosis
- IL-1:
-
Interleukin-1
- ICE:
-
IL-1 converting enzyme
- IFI16:
-
Interoferon–gamma-inducible protein-1
- IRE1α:
-
Inositol-requiring enzyme/inositol-requiring transmembrane kinase/endoribonuclease 1 alpha
- JNK:
-
C-JUN-N–terminal kinase
- JIK:
-
JNK-inhibitory kinase
- LRRs :
-
Leucine-rich repeats
- MC159 :
-
FLICE inhibitory protein (Mollusccum contagiosum virus)
- MAVS:
-
Mitochondrial antiviral-signaling protein
- MEKK1:
-
Mitogen-activated protein kinase kinase kinase inhibitor1
- NLS:
-
N-terminal nuclear localization signals
- NAFLD:
-
Non-alcoholic fatty liver disease
- NUAK:
-
Member of AMPK (AMP-activated protein kinase)
- NOD:
-
Nucleotide oligomerizatin domain
- NLRs :
-
Nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors
- NLRP-3:
-
NOD-LRR and pyrin domain containg protein-3
- NAC:
-
N-acetyl-L-cysteine
- NBA-CARD:
-
Nijmegan modification of Bethesda assay
- NOD2:
-
Nucleotide-binding oligomerization domain containing protein-2
- NRADD:
-
Neurotrophin receptor alike death domain protein
- NF-kB:
-
Nuclear factor kappa light chain enhancer of activated b-cells
- ORF-6:
-
Accessory protein 6/non-structural protein 6
- ORF-3b:
-
Non-structural protein 3b/accessory protein 3b
- Orf-3a:
-
Non-structural protein 3a/accessory protein 3a
- ORF-7a:
-
Non-structural protein 7a/accessory protein 7a
- ORF-4:
-
Non-structural protein 4/accessory protein 4
- PRPA:
-
Poly-ADP ribose polymerase
- PEDE:
-
Phosphodiesterase
- PYD:
-
Pyrin domain
- PARPs :
-
Poly(ADP-ribose) polymerase inhibitors
- PD:
-
Parkinson’s disease
- P21 :
-
Ras protein/cyclin-dependent kinase inhibitor 1
- PRRs :
-
Pattern recognition receptors
- RIG-1:
-
Retinoic acid-inducible gene 1
- RT-PCR:
-
Reverse transcription polymerase chain reaction
- RNA:
-
Ribonucleic acid
- ROS:
-
Reactive oxygen species
- siRNA:
-
Small interfering RNA
- sf9:
-
Clonal isolate of Spodoptera frugiperda sf21 cells
- SERPINB1:
-
Serpin family b member 1
- ST14A:
-
Suppressor of tumorigenicity 14 protein homolog
- SARS-CoV:
-
Severe acute respiratory syndrome-coronavirus
- SAT:
-
Sulfate adenylyl transferase
- SARSX4:
-
SARs coronavirus X4 like protein domain
- SADS-CoV:
-
Swine acute diarrhea syndrome coronavirus
- TLR-4:
-
Toll-like receptor-4
- TLR3-TRIF:
-
Toll-like receptor-3-TRIF
- TRIF:
-
TIR-domain-containing adaptor-inducing interferon-β
- TRAF2:
-
Tumor necrosis factor receptor-associated factor-2
- UPR:
-
Unfolded protein response
- UVB:
-
Ultraviolet
- XIAP:
-
X-linked inhibitor of apoptosis protein YAVD
- AFC:
-
N-Acetyl-Tyr-Val-Ala-Asp-7-Amido-4-trifluro-methylcoumarin
References
McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5(4):a008656
Galluzzi L, Lopez-Soto A, Kumar S, Kroemer G (2016) Caspases connect cell-death signaling to organismal homeostasis. Immunity 44(2):221–231
Cookson BT, Brennan MA (2001) Pro-inflammatory programmed cell death. Trends Microbiol 3(9):113–114
Behzadi P, Ranjbar R (2015) Caspase and apoptosis. Cell 4(7):11–13
Dhani S, Zhao Y, Zhivotovsky B (2021) A long way to go: caspase inhibitors in clinical use. Cell Death Dis 12(10):949
Kayagaki N, Warming S, Lamkanfi M, Walle LV, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479(7371):117–121
Bergsbaken T, Cookson BT (2007) Macrophage activation redirects yersinia-infected host cell death from apoptosis to caspase-1-dependent pyroptosis. PLoS Pathog 3:e161
Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nunez G (2007) Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella infected macrophages. PLoS Pathog 3:e111
Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501
Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P (2004) Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol 173(5):2976–2984
Salmena L, Lemmers B, Hakem A, Matysiak-Zablocki E, Murakami K, Au PB, Berry DM, Tamblyn L, Shehabeldin A, Migon E, Wakeham A (2003) Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 17(7):883–895
Salmena L, Hakem R (2005) Caspase-8 deficiency in T cells leads to a lethal lymphoinfiltrative immune disorder. J Exp Med 202(6):727–732
Okuyama R, Nguyen BC, Talora C, Ogawa E, di Vignano AT, Lioumi M, Chiorino G, Tagami H, Woo M, Dotto GP (2004) High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell 6(4):551–562
Holleman A, Boer ML, Kazemier KM, Beverloo HB, von Bergh AR, Janka-Schaub GE, Pieters R (2005) Decreased PARP and procaspase-2 protein levels are associated with cellular drug resistance in childhood acute lymphoblastic leukemia. Blood 106(5):1817–1823
Ho LH, Taylor R, Dorstyn L, Cakouros D, Bouillet P, Kumar S (2009) A tumor suppressor function for caspase-2. Proc Natl Acad Sci USA 106:5336–5341
Kim MS, Chung NG, Yoo NJ, Lee SH (2011) Somatic mutation of proapoptotic caspase-2 gene is rare in acute leukemias and common solid cancers. Eur J Haematol 86:449–450
Xu HL, Xu WH, Cai Q, Feng M, Long J, Zheng W, Xiang YB, Shu XO (2009) Polymorphisms and haplotypes in the caspase-3, caspase-7, and caspase-8 genes and risk for endometrial cancer: a population-based, case-control study in a Chinese population. Cancer Epidemiol Biomarkers Prev 18(7):2114–2122
Kim HS, Lee JW, Soung YH, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Jeong SW, Nam SW (2003) Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 125(3):708–715
Krajewska M, Kim H, Shin E, Kennedy S, Duffy MJ, Wong YF, Marr D, Mikolajczyk J, Shabaik A, Meinhold-Heerlein I, Huang X (2005) Tumor-associated alterations in caspase-14 expression in epithelial malignancies. Clin Cancer Res 11(15):5462–5471
Wu M, Kodani I, Dickinson D, Huff F, Ogbureke KU, Qin H, Arun S, Dulebohn R, Al-Shabrawey M, Tawfik A, Prater S (2009) Exogenous expression of caspase-14 induces tumor suppression in human salivary cancer cells by inhibiting tumor vascularization. Anticancer Res 29(10):3811–3818
Parsons MJ, McCormick L, Janke L, Howard A, Bouchier-Hayes L, Green DR (2013) Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice. Cell Death Differ 20:1174–1182
Stupack DG (2013) Caspase-8 as a therapeutic target in cancer. Cancer Lett 332:133–140
Jang JS, Kim KM, Choi JE, Cha SI, Kim CH, Lee WK, Kam S, Jung TH, Park JY (2008) Identification of polymorphisms in the Caspase-3 gene and their association with lung cancer risk. Mol Carcinog 47:383–390
Tiwari M, Sharma LK, Vanegas D, Callaway DA, Bai Y, Lechleiter JD, Herman B (2014) A nonapoptotic role for CASP2/caspase 2: modulation of autophagy. Autophagy 10(6):1054–1070
Zhang Y, Padalecki SS, Chaudhuri AR, De Waal E, Goins BA, Grubbs B, Ikeno Y, Richardson A, Mundy GR, Herman B (2007) Caspase-2 deficiency enhances aging-related traits in mice. Mech Ageing Dev 128(2):213–221
Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6):817–829
Shaham S (1998) Identification of multiple Caenorhabditis elegans caspases and their potential roles in proteolytic cascades. J Biol Chem 273:35109–35117
Li J, Yuan J (2008) Caspases in apoptosis and beyond. Oncogene 27(48):6194–6206
Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75:641–652
Chinnaiyan AM, O’Rourke K, Lane BR, Dixit VM (1997) Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science 275:1122–1126
Parrish AB, Freel CD, Kornbluth S (2013) Cellular mechanisms controlling caspase activation and function. Cold Spring Harb Perspect Biol 5(6):a008672
Shi L, Chen G, MacDonald G, Bergeron L, Li H, Miura M, Rotello RJ, Miller DK, Li P, Seshadri T, Yuan J (1996) Activation of an interleukin 1 converting enzyme-dependent apoptosis pathway by granzyme B. Proc Natl Acad Sci 93:11002–11007
Kolodgie FD, Narula J, Burke AP, Haider N, Farb A, Hui-Liang Y, Smialek J, Virmani R (2000) Localization of apoptotic macrophages at the site of plaque rupture in sudden coronary death. Am J Pathol 157:1259–1268
Frantz S, Ducharme A, Sawyer D, Rohde LE, Kobzik L, Fukazawa R, Tracey D, Allen H, Lee RT, Kelly RA (2003) Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction. J Mol Cell Cardiol 35:685–694
Liu XH, Kwon D, Schielke GP, Yang GY, Silverstein FS, Barks JD (1999) Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood Flow Metab 19:1099–1108
Yang GY, Schielke GP, Gong C, Mao Y, Ge HL, Liu XH, Betz AL (1999) Expression of tumor necrosis factor-a and intercellular adhesion molecule-1 after focal cerebral ischemia in interleukin-1b converting enzyme deficient mice. J Cereb Blood Flow Metab 19:1109–1117
Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM (2003) Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia induced neuronal cell death. Proc Natl Acad Sci 100:16012–16017
Soung YH, Lee JW, Kim SY, Park WS, Nam SW, Lee JY, Yoo NJ, Lee SH (2004) Somatic mutations of CASP3 gene in human cancers. Hum Genet 115:112–115
Hosgood HD 3rd, Baris D, Zhang Y, Zhu Y, Zheng T, Yeager M, Welch R, Zahm S, Chanock S, Rothman N, Lan Q (2008) Caspase polymorphisms and genetic susceptibility to multiplemyeloma. Hematol Oncol 26:148–151
Lan Q, Zheng T, Chanock S, Zhang Y, Shen M, Wang SS, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M (2007) Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma. Carcinogenesis 28:823–827
Lee JW, Kim MR, Soung YH, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2006) Mutational analysis of the CASP6 gene in colorectal and gastric carcinomas. APMIS 114:646–650
Yoo NJ, Lee JW, Kim YJ, Soung YH, Kim SY, Nam SW, Park WS, Lee JY, Lee SH (2004) Loss of caspase-2, -6 and -7 expression in gastric cancers. APMIS 112:330–335
Soung YH, Lee JW, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ, Park YG, Nam SW (2003) Inactivating mutations of CASPASE-7 gene in human cancers. Oncogene 22:8048–8052
Lee WK, Kim JS, Kang HG, Cha SI, Kim DS, Hyun DS, Kam S, Kim CH, Jung TH, Park JY (2009) Polymorphisms in the Caspase7 gene and the risk of lung cancer. Lung Cancer 65:19–24
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267–276
Yeh WC, Pompa JL, McCurrach ME, Shu HB, Elia AJ, Shahinian A, Ng M, Wakeham A, Khoo W, Mitchell K, El-Deiry WS (1998) FADD: Essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science 279:1954–1958
Beisner DR, Ch’en IL, Kolla RV, Hoffmann A, Hedrick SM (2005) Cutting edge: Innate immunity conferred by B cells is regulated by caspase-8. J Immunol 175:3469–3473
Kovalenko A, Kim JC, Kang TB, Rajput A, Bogdanov K, Dittrich-Breiholz O, Kracht M, Brenner O, Wallach D (2009) Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J Exp Med 206:2161–2177
Lee P, Lee DJ, Chan C, Chen SW, Ch’en I, Jamora C (2009) Dynamic expression of epidermal caspase 8 simulates a wound healing response. Nature 458:519–523
Li C, Lasse S, Lee P, Nakasaki M, Chen SW, Yamasaki K, Gallo RL, Jamora C (2010) Development of atopic dermatitis like skin disease from the chronic loss of epidermal caspase-8. Proc Natl Acad Sci 107:22249–22254
Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–372
Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471:363–367
Zhang H, Zhou X, McQuade T, Li J, Chan FK, Zhang J (2011) Functional complementation between FADD and RIP1 in embryos and lymphocytes. Nature 471:373–376
Kelly JL, Novak AJ, Fredericksen ZS, Liebow M, Ansell SM, Dogan A, Wang AH, Witzig TE, Call TG, Kay NE, Habermann TM (2010) Germline variation in apoptosis pathway genes and risk of non-Hodgkin’s lymphoma. Cancer Epidemiol Biomarkers Prev 19:2847–2858
Lan Q, Morton LM, Armstrong B, Hartge P, Menashe I, Zheng T, Purdue MP, Cerhan JR, Zhang Y, Grulich A, Cozen W (2009) Genetic variation in caspase genes and risk of non-Hodgkin lymphoma: a pooled analysis of 3 population based case-control studies. Blood 114:264–267
Park JY, Park JM, Jang JS, Choi JE, Kim KM, Cha SI, Kim CH, Kang YM, Lee WK, Kam S, Park RW, Kim IS, Lee JT, Jung TH (2006) Caspase 9 promoter polymorphisms and risk of primary lung cancer. Hum Mol Genet 15(12):1963–1971
Shin MS, Kim HS, Kang CS, Park WS, Kim SY, Lee SN, Lee JH, Park JY, Jang JJ, Kim CW, Kim SH (2002) Inactivating mutations of CASP10 gene in non-Hodgkin lymphomas. Blood 99:4094–4099
Kim MS, Oh JE, Min CK, Lee S, Chung NG, Yoo NJ, Lee SH (2009) Mutational analysis of CASP10 gene in acute leukaemias and multiplemyelomas. Pathology 41:484–487
Oh JE, Kim MS, Ahn CH, Kim SS, Han JY, Lee SH, Yoo NJ (2010) Mutational analysis of CASP10 gene in colon, breast, lung and hepatocellular carcinomas. Pathology 42:73–76
Park WS, Lee JH, Shin MS, Park JY, Kim HS, Kim YS, Lee SN, XiaoW PCH, Lee SH (2002) Inactivating mutations of the caspase-10 gene in gastric cancer. Oncogene 21:2919–2925
Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, Yin H, von Andrian UH, Mitchison T, Yuan J (2007) Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization. Nat Cell Biol 9:276–286
Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J (1998) Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92:501–509
Scott AM, Saleh M (2007) The inflammatory caspases: guardians against infections and sepsis. Cell Death Differ 14:23–31
Saleh M, Vaillancourt JP, Graham RK, Huyck M, Srinivasula SM, Alnemri ES, Steinberg MH, Nolan V, Baldwin CT, Hotchkiss RS, Buchman TG (2004) Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429:75–79
Denecker G, Ovaere P, Vandenabeele P, Declercq W (2008) Caspase-14 reveals its secrets. J Cell Biol 180:451–458
Denecker G, Hoste E, Gilbert B, Hochepied T, Ovaere P, Lippens S, Van den Broecke C, Van Damme P, D’Herde K, Hachem JP, Borgonie G (2007) Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 9:666–674
Salvesen GS, Dixit VM (1999) Caspase activation: the induced-proximity model. PNAS USA 96(20):10964–10967
Harvey NL, Kumar S (1998) Role of caspase in apoptosis. Adv Biochem Eng Biotechnol 62:107–128
Troy CM, Jean YY (2013) Caspase-2, structural chemistry. In: Rawlings ND, Salvesen G (eds) Handbook of proteolytic enzymes, 3rd edn. Chapter 506, pp 2243–2247
Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (2002) Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem 277(16):13430–13437
Bonzon C, Bouchier-Hayes L, Pagliari LJ, Green DR, Newmeyer DD (2006) Caspase-2–induced apoptosis requires bid cleavage: a physiological role for bid in heat shock–induced death. Mol Biol Cell 17(5):2150–2157
Bouchier-Hayes L, Oberst A, McStay GP, Connell S, Tait SW, Dillon CP, Flanagan JM, Beere HM, Green DR (2009) Characterization of cytoplasmic caspase-2 activation by induced proximity. Mol Cell 35(6):830–840
Tu S, McStay GP, Boucher LM, Mak T, Beere HM, Green DR (2006) In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat Cell Biol 8(1):72–77
Machado MV, Michelotti GA, Jewell ML, Pereira TA, Xie G, Premont RT, Diehl AM (2016) Caspase-2 promotes obesity, the metabolic syndrome and nonalcoholic fatty liver disease. Cell Death Dis 7(2):e2096
Johnson ES, Lindblom KR, Robeson A, Stevens RD, Ilkayeva OR, Newgard CB, Kornbluth S, Andersen JL (2013) Metabolomic profiling reveals a role for caspase-2 in lipoapoptosis. J Biol Chem 288(20):14463–14475
Bouchier-Hayes L (2010) The role of caspase-2 in stress-induced apoptosis. J Cell Mol Med 14(6A):1212–1224
Boatright KM, Salvesen GS (2003) Mechanisms of caspase activation. Curr Opin Cell Biol 15(6):725–731
Beaudouin J, Liesche C, Aschenbrenner S, Hörner M, Eils R (2013) Caspase-8 cleaves its substrates from the plasma membrane upon CD95-induced apoptosis. Cell Death Differ 20(4):599–610
Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ (2002) Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419(6905):395–399
Frisch SM (2008) Caspase-8: fly or die. Cancer Res 68(12):4491–4493
Zhivotovsky B, Samali A, Gahm A, Orrenius S (1999) Caspases: their intracellular localization and translocation during apoptosis. Cell Death Differ 6:644–651
Kuida K (2000) Caspase-9. Int J Biochem Cell Biol 32(2):121–124
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94(3):339–352
Kuwahara D, Tsutsumi K, Oyake D, Ohta T, Nishikawa H, Koizuka I (2003) Inhibition of caspase-9 activity and Apaf-1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells. Auris Nasus Larynx 30:85S-88S
Mueller T, Voigt W, Simon H, Fruehauf A, Bulankin A, Grothey A, Schmoll HJ (2003) Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer. Cancer Res 63:513–521
Chee JL, Saidin S, Lane DP, Leong SM, Noll JE, Neilsen PM, Phua YT, Gabra H, Lim TM (2013) Wild-type and mutant p53 mediate cisplatin resistance through interaction and inhibition of active caspase-9. Cell Cycle 12:278–288
Tamaki H, Harashima N, Hiraki M, Arichi N, Nishimura N, Shiina H, Naora K, Harada M (2014) Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition. Oncotarget 5:11399–11412
Rohn TT, Rissman RA, Davis MC, Kim YE, Cotman CW, Head E (2002) Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 11(2):341–354
Fernandes-Alnemri T, Armstrong RC, Krebs J, Srinivasula SM, Wang L, Bullrich F, Fritz LC, Trapani JA, Tomaselli KJ, Litwack G, Alnemri ES (1996) In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. PNAS USA 93(15):7464–7469
Wachmann K, Pop C, van Raam BJ, Drag M, Mace PD, Snipas SJ, Zmasek C, Schwarzenbacher R, Salvesen GS, Riedl SJ (2010) Activation and specificity of human caspase-10. Biochemistry 49(38):8307–8315
Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ (2001) Caspase-10 is an initiator caspase in death receptor signaling. PNAS USA 98(24):13884–13888
Nicholson DW, Thornberry NA (1997) Caspases: killer proteases. Trends Biochem Sci 22:299–306
Benchoua A, Guégan C, Couriaud C, Hosseini H, Sampaı̈o N, Morin D, Onténiente B (2001) Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 21(18):7127–7134
O’Donovan N, Crown J, Stunell H, Hill AD, McDermott E, O’Higgins N, Duffy MJ (2003) Caspase 3 in breast cancer. Clin Cancer Res 9(2):738–742
Khan S, Ahmed K, Alshammari EMA, Adnan M, Baig MH, Lohani M, Haque S (2015) Implication of caspase- 3 as a common therapeutic target for multi neurodegenerative disorders and its inhibition using nonpeptidyl natural compounds. Biomed Res Int 2015:1–9
Kanazawa I (2001) How do neurons die in neurodegenerative diseases? Trends Mol Med 7(8):339–344
Li M, Ona VO, Guégan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM (2000) Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288(5464):335–339
Martin LJ, Price AC, Kaiser A, Shaikh AY, Liu Z (2000) Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (review). Int J Mol Med 5(1):3–13
Boston-Howes W, Gibb SL, Williams EO, Pasinelli P, Brown RH, Trotti D (2006) Caspase-3 cleaves and inactivates the glutamate transporter EAAT2. J Biol Chem 281(20):14076–14084
Hartmann A, Hunot S, Michel PP, Muriel MP, Vyas S, Faucheux BA, Mouatt-Prigent A, Turmel H, Srinivasan A, Ruberg M, Evan GI (2000) Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc Natl Acad Sci 97(6):2875–2880
Tiso N, Pallavicini A, Muraro T, Zimbello R, Apolloni E, Valle G, Lanfranchi G, Danieli GA (1996) Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. Biochem Biophys Res Commun 225(3):983–989
Wang XJ, CaO Q, Liu X, Wang KT, Mi W, Zhang Y, Li LF, LeBlanc AC, Su XD (2010) Crystal structures of human caspase6 reveal a new mechanism for intramolecular cleavage self-activation. EMBO Rep 11(11):841–847
Graham RK, Ehrnhoefer DE, Hayden MR (2011) Caspase-6 and neurodegeneration. Trends Neurosci 34(12):646–656
Bagbay KB, Hardy JA (2017) Multiple proteolytic events in caspase-6 self- activation impact conformations of discreate structural regions. PANS 114(38):E7977–E7986
Velazquez-Delgado EM, Hardy JA (2012) Phosphorylation regulates assembly of the caspase-6 substrate-binding groove. Structure 20(4):742–751
Suzuki A, Kusakai GI, Kishimoto A, Shimojo Y, Miyamoto S, Ogura T, Ochiai A, Esumi H (2004) Regulation of caspase-6 and FLIP by the AMPK family member ARK5. Oncogene 23(42):7067–7075
Wang XJ, Cao Q, Zhang Y, Su XD (2015) Activation and regulation caspase-6 and its role in neurodegenerative disease. Annu Rev pharmacol Toxicol 55:553–572
Novak MJ, Tabrizi SJ (2010) Huntington’s disease. BMJ 340:c3109
The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:971–983
Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125(6):1179–1191
Wellington CL, Ellerby L, Savill J, Roy S, Leavitt B, Cattaneo E, Hackam A, Sharp A, Thornberry N, Nicholson DW, Bredesen DE (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J Biol Chem 275(26):19831–19838
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies SW, Bates GP (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87(3):493–506
Hackam AS, Singaraja R, Wellington CL, Metzler M, McCutcheon K, Zhang T, Kalchman M, Hayden MR (1998) The influence of huntingtin protein size on nuclear localization and cellular toxicity. J Cell Biol 141(5):1097–1105
Wellington CL, Ellerby LM, Gutekunst CA, Rogers D, Warby S, Graham RK, Loubser O, van Raamsdonk J, Yang YZ, Gafni J, Bredesen D (2002) Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington’s disease. J Neurosci 22(18):7862–7872
Graham RK, Deng Y, Carroll J, Vaid K, Cowan C, Pouladi MA, Metzler M, Bissada N, Wang L, Faull RL, Gray M (2010) Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci 30(45):15019–15029
Tanzi RE, Bertram L (2005) Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 120:545–555
Goedert M, Spillantini MG (2006) A century of Alzheimer’s disease. Science 314:777–781
Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC (2004) Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer’s disease. Am J Pathol 165:523–531
Albrecht S, Bourdeau M, Bennett D, Mufson EJ, Bhattacharjee M, LeBlanc AC (2007) Activation of caspase-6 in aging and mild cognitive impairment. Am J Pathol 170:1200–1209
Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T (1997) Changes of p53 in the brains of patients with Alzheimer’s disease. Biochem Biophys Res Commun 232:418–421
MacLachlan TK, El-Deiry WS (2002) Apoptotic threshold is lowered by p53 transactivation of caspase-6. Proc Natl Acad Sci USA 99:9492–9497
Pompl PN, Yemul S, Xiang Z, Ho L, Haroutunian V, Purohit D, Mohs R, Pasinetti GM (2003) Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch Neurol 60(3):369–376
Albrecht S, Bogdanovic N, Ghetti B, Winblad B, LeBlanc AC (2009) Caspase-6 activation in familial Alzheimer disease brains carrying amyloid precursor protein or presenilin I or presenilin II mutations. J Neuropathol Exp Neurol 68:1282–1293
Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH (2013) Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol 14(1):1–9
Hardy JA, Wells JA (2009) “Dissecting an allosteric switch in caspase-7 using chemical and mutational probes. J Biol Chem 284(38):26063–26069
Wei X, Xie F, Zhou X, Wu Y, Yan H, Liu T, Huang J, Wang F et al (2022) Role of pyroptosis in inflammation and cancer. Cell Mol Immunol 19(9):971–992. https://doi.org/10.1038/s41423-022-00905-x
Jorgensen I, Miao EA (2015) Pyroptotic Cell death defends against intracellular pathogens. Immunol Rev 265(1):130–142
Dagenais M, Skeldon A, Saleh M (2012) The inflammasome: in memory of Dr. Jurg Tschopp Cell death Differ 19(1):5–12
Schroder K, Tschopp J (2010) The inflammasome. Cell 140(60):821–832
Clark AC (2016) Caspase allostery and conformational selection. Chem Rev 116(11):6666–6706
Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose- Grima M, Erickson S, Dixit VM (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf“. Nature 430(6996):213–218
Kumaresan V, Ravichandran G, Nizam F, Dhayanithi NB, Arasu MV, Al-Dhabi NA, Harikrishnan R, Arockiaraj J (2016) Multifuctional murrel caspase-1, 2, 3, 8 and 9: conservation, uniqueness and their pathogen- induced expression pattern. Fish Shellfish Immun 49:493–504
Sollberger G, Strittmatter GE, Garstkiewicz M, Sand J, Beer HD (2014) Caspase-1: the inflammasome and beyond. Innate immune 20(2):115–125
Wilson KP, Black JA, Thomson JA, Kim EE, Griffith JP, Navia MA, Murcko MA, Chambers SP, Aldape RA, Raybuck SA (1994) Structure and mechanism of interleukin-1 beta converting enzyme. Nature 370(6487):270–275
Romanowski MJ, Scheer JM, O’Brien T, McDowell RS (2004) Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding. Structure 12(8):1361–1371
Compan V, Martín-Sánchez F, Baroja-Mazo A, López-Castejón G, Gomez AI, Verkhratsky A, Brough D, Pelegrín P (2015) Apoptosis-associated speck-like protein containing a CARD forms specks but does not activate caspase-1 in the absence of NLRP3 during macrophage swelling. J Immunol 194(3):1261–1273
Lu A, Li Y, Schmidt FI, Yin Q, Chen S, Fu TM, Tong AB, Ploegh HL, Mao Y, Wu H (2016) Molecular basis of a new capping mechanism. Nat Struct Mol Biol 23(5):416–425
Eldridge MJ, Shenoy AR (2015) Antimicrobial inflammasomes: unified signalling against diverse bacterial pathogens. Curr Opin Microbiol 23:32–41
Mathiak G, Grass G, Herzmann T, Luebke T, Zetina CC, Boehm SA, Bohlen H, Neville LF, Hoelscher AH (2000) Caspase-1-inhibitor ac-YVAD-cmk reduces LPS-lethality in rats without affecting haematology or cytokine responses. Br J Pharmacol 131(3):383–386
Friedlander RM (2000) Role of caspase 1 in neurologic disease. Arch Neurol 57(9):1273–1276
Kamens J, Paskind M, Hugunin M, Talanian RV, Allen H, Banach D, Bump N, Hackett M, Johnston CG, Li P, Mankovich JA (1995) Identification and characterization of ICH-2, a novel member of the interleukin-1β-converting enzyme family of cysteine proteases (∗). J Biol Chem 270(25):15250–15256
Munday NA, Vaillancourt JP, Ali A, Casano FJ, Miller DK, Molineaux SM, Yamin TT, Violeta LY, Nicholson DW (1995) Molecular cloning and pro-apoptotic activity of ICErelII and ICErelIII, members of the ICE/CED-3 family of cysteine proteases (∗). J Biol Chem 270(26):15870–15876
Kamada S, Washida M, Hasegawa JI, Kusano H, Funahashi Y, Tsujimoto Y (1997) Involvement of caspase-4 (-like) protease in Fas-mediated apoptotic pathway. Oncogene 15(3):285–290
Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403(6765):98–103
Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol 165(3):347–356
Boyce M, Yuan J (2006) Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ 13(3):363–373
Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA, Cleveland JL, Giles FJ, McConkey DJ (2008) Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA. Blood 112(7):2917–2926
Jiang CC, Chen LH, Gillespie S, Wang YF, Kiejda KA, Zhang XD, Hersey P (2007) Inhibition of MEK sensitizes human melanoma cells to endoplasmic reticulum stress-induced apoptosis. Cancer Res 67(20):9750–9761
Pyrko P, Kardosh A, Wang W, Xiong W, Schönthal AH, Chen TC (2007) HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res 67(22):10920–10928
Rahmani M, Davis EM, Crabtree TR, Habibi JR, Nguyen TK, Dent P, Grant S (2007) The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress. Mol Cell Biol 27(15):5499–5513
Obeng EA, Boise LH (2005) Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. J Biol Chem 280(33):29578–29587
Mao ZG, Jiang CC, Yang F, Thorne RF, Hersey P, Zhang XD (2010) TRAIL-induced apoptosis of human melanoma cells involves activation of caspase-4. Apoptosis 15(10):1211–1222
Lakshmanan U, Porter AG (2007) Caspase-4 interacts with TNF receptor-associated factor 6 and mediates lipopolysaccharide-induced NF-κB-dependent production of IL-8 and CC chemokine ligand 4 (macrophage-inflammatory protein-1β). J Immunol 179(12):8480–8490
Faucheu C, Blanchet AM, Collard-Dutilleul V, Lalanne JL, Diu-Hercend A (1996) Identification of a cysteine protease closely related to interleukin-1β-converting enzyme. Eur J Biochem 236(1):207–213
Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol cell 10(2):417–426
Martinon F, Mayor A, Tschopp J (2009) The inflammasomes: guardians of the body. Annu Rev Immunol 27:229–265
Martinon F, Tschopp J (2007) Inflammatory caspases and inflammasomes: master switches of inflammation. Cell Death Differ 14(1):10–22
Latz E (2010) The inflammasomes: mechanisms of activation and function. Curr Opin Immunol 22(1):28–33
Lin XY, Choi MS, Porter AG (2000) Expression analysis of the human caspase-1 subfamily reveals specific regulation of the CASP5 gene by lipopolysaccharide and interferon-γ. J Biol Chem 275(51):39920–39926
Sutterwala FS, Ogura Y, Flavell RA (2007) The inflammasome in pathogen recognition and inflammation. J Leukoc Biol 82(2):259–264
Kumar S, White DL, Takai S, Turczynowicz S, Juttner CA, Hughes TP (1995) Apoptosis regulatory gene NEDD2 maps to human chromosome segment 7q34-35, a region frequently affected in haematological neoplasms. Hum Genet 95:641–644
Van Opdenbosch N, Lamkanfi M (2019) Caspases in cell death, inflammation, and disease. Immunity 50(6):1352–1364
Berkun Y, Karban A, Padeh S, Pras E, Shinar Y, Lidar M, Livneh A, Bujanover Y (2012) NOD2/CARD15 gene mutations in patients with familial Mediterranean fever In Seminars in arthritis and rheumatism. WB Saunders 42(1):84–88
Junjun G, James AW (2013) Caspase-4 and caspase-5. In: Rawlings ND, Salvesen G (eds) Handbook of proteolytic enzymes, 3rd edn, pp 3265–3270
Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, Leong JM, Fitzgerald KA (2012) TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150(3):606–619
Broz P, Monack DM (2013) Noncanonical inflammasomes; caspase-11 activation and effector Mechanism. PLoS Pathog 9(2):e1003144
Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszyński A, Forsberg LS (2013) Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341(6151):1246–1249
Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L, Shao F (2014) Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 7521:187–192
Crowley SM, Vallance BA, Knodler LA (2017) Noncanonical inflammasomes: antimicrobial defense that does not play by the rules. Cell Microbiol 19(4):1–9
Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526(7575):660–665
Aglietti RA, Estevez A, Gupta A, Ramirez MG, Liu PS, Kayagaki N, Ciferri C, Dixit VM, Dueber EC (2016) GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc Natl Acad Sci 113(28):7858–7863
Lee BL, Stowe IB, Gupta A, Kornfeld OS, Roose-Girma M, Anderson K, Warming S, Zhang J, Lee WP, Kayagaki N (2018) Caspase-11 auto-proteolysis is crucial for noncanonical inflammasome activation. J Exp Med 215(9):2279–2288
Ikawa K, Sugimura K (2018) AIP1 and cofilin ensure a resistance to tissue tension and promote directional cell rearrangement. Nat commun 9(1):1–4
Fischer H, Koenig U, Eckhart L, Tschachler E (2002) Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun 293(2):722–726
Roy S, Sharom JR, Houde C, Loisel TP, Vaillancourt JP, Shao W, Saleh M, Nicholson DW (2008) Confinement of caspase-12 proteolytic activity to autoprocessing. PNAS 105(11):4133–4138
Kalai M, Lamkanfi M, Denecker G, Boogmans M, Lippens S, Meeus A, Declercq W, Vandenabeele P (2003) Regulation of the expression and processing of caspase. J Cell Biol 62(3):457–467
Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276(17):13935–13940
Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13:1211–1233
Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12:1812–1824
Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D (1998) Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17:5708–5717
Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666
Westwick JK, Weitzel C, Minden A, Karin M, Brenner DA (1994) Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem 269(42):26396–26401
Latinis KM, Koretzky GA (1996) Fas ligation induces apoptosis and Jun kinase activation independently of CD45 and Lck in human T cells. Blood 87:871–875
Gupta S, Campbell D, Derijard B, Davis RJ (1995) Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267(5196):389–393
Yarza R, Vela S, Solas M, Ramirez MJ (2016) c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front Pharmacol 6:321
Xie P (2013) TRAF molecules in cell signaling and in human diseases. J Mol Signal 8(1):1–31
Lamkanfi M, Kalai M, Vandenabeele P (2004) Cell death and differentiation. Cell Death Differ 2:365–368
Shalini S, Dorstyn L, Dawar S, Kumar S (2015) Old, new and emerging functions of caspases. Cell Death Differ 22(4):526–539
Bian ZM, Elner SG, Elner VM (2008) Regulated expression of caspase-12 gene in human retinal pigment epithelial cells suggests its immunomodulating role. Invest Ophthalmol Vis Sci 49(12):5593–5601
Koenig U, Eckhart L, Tschachler E (2001) Evidence that caspase-13 is not a human but a bovine gene. Biochem Bioph Res Co 285(5):1150–1154
Humke EW, Ni J, Dixit VM (1998) ERICA, a novel FLICE-activatable caspase. J Boil Chem 273(25):15702–15707
Hu S, Snipas SJ, Vincenz C, Salvesen G, Dixit VM (1998) Caspase-14 is a novel developmentally regulated protease. J Biol Chem 273(45):29648–29653
Lamkanfi M, Declercq W, Kalai M, Saelens X, Vandenabeele P (2002) Alice in caspase land. A phylogenetic analysis of caspases from worm to man. Cell Death Differ 9:358–361
Van de Craen M, Van Loo G, Pype S, Van Criekinge W, Molemans F, Fiers W, Declercq W, Vandenabeele P (1998) Identification of a new caspase homologue: caspase-14. Cell Death Diff 5(10):838–846
Eckhart L, Declercq W, Ban J, Rendl M, Lengauer B, Mayer C, Lippens S, Vandenabeele P, Tschachler E (2000) Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation. J Invest Dermatol 115:1148–1151
Lippens S, Kockx M, Knaapen M, Mortier L, Polakowska R, Verheyen A, Garmyn M, Zwijsen A, Formstecher P, Huylebroeck D, Vandenabeele P (2000) Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing. Cell Death Differ 7(12):1218–1224
Lippens S, Kockx M, Denecker G, Knaapen M, Verheyen A, Christiaen R, Tschachler E, Vandenabeele P, Declercq W (2004) Vitamin D3 induces caspase-14 expression in psoriatic lesions and enhances caspase-14 processing in organotypic skin cultures. Am J Pathol 165(3):833–841
Rendl M, Ban J, Mrass P, Mayer C, Lengauer B, Eckhart L, Declerq W, Tschachler E (2002) Caspase-14 expression by epidermal keratinocytes is regulated by retinoids in a differentiation-associated manner. J Invest Dermatol 119:1150–1155
Alibardi L, Tschachler E, Eckhart L (2005) Distribution of caspase-14 in epidermis and hair follicles is evolutionarily conserved among mammals. Anat Rec A Discov Mol Cell Evol Biol 286:962–973
Alibardi L, Dockal M, Reinisch C, Tschachler E, Eckhart L (2004) Ultrastructural localization of caspase-14 in human epidermis. J Histochem Cytochem 52:1561–1574
Lippens S, VandenBroecke C, Van Damme E, Tschachler E, Vandenabeele P, Declercq W (2003) Caspase-14 is expressed in the epidermis, the choroid plexus, the retinal pigment epithelium and thymic Hassall’s bodies. Cell Death Differ 10:257–259
Krajewska M, Rosenthal RE, Mikolajczyk J, Stennicke HR, Wiesenthal T, Mai J, Naito M, Salvesen GS, Reed JC, Fiskum G, Krajewski S (2004) Early processing of Bid and caspase-6, -8, -10, -14 in the canine brain during cardiac arrest and resuscitation. Exp Neurol 189:261–279
Kam DW, Charles AK, Dharmarajan AM (2005) Caspase-14 expression in the human placenta. Reprod Biomed Online 11:236–243
Seidelin JB, Nielsen OH (2006) Expression profiling of apoptosis-related genes in enterocytes isolated from patients with ulcerative colitis. APMIS 114:508–517
Selicharova I, Smutna K, Sanda M, Ubik K, Matouskova E, Bursikova E, Brozova M, Vydra J, Jiracek J (2007) 2-DE analysis of a new human cell line EM-G3 derived from breast cancer progenitor cells and comparison with normal mammary epithelial cells. Proteomics 7:1549–1559
Eckhart L, Ban J, Fischer H, Tschachler E (2000) Caspase-14: analysis of gene structure and mRNA expression during keratinocyte differentiation. Biochem Biophys Res Commun 277:655–659
Pistritto G, Jost M, Srinivasula SM, Baffa R, Poyet JL, Kari C, Lazebnik Y, Rodeck U, Alnemri ES (2002) Expression and transcriptional regulation of caspase-14 in simple and complex epithelia. Cell Death Differ 9:995–1006
Kuechle MK, Predd HM, Fleckman P, Dale BA, Presland RB (2001) Caspase-14, a keratinocyte specific caspase: mRNA splice variants and expression pattern in embryonic and adult mouse. Cell Death Differ 8:868–870
Yamamoto M, Miyai M, Matsumoto Y, Tsuboi R, Hibino T (2012) Kallikrein-related peptidase-7 regulates caspase-14 maturation during keratinocyte terminal differentiation by generating an intermediate form. J Biol Chem 287(39):32825–32834
McGrath JA, Eady RA, Pope FM (2004) Anatomy and organization of human skin. In: Burns T, Breathnach S, Cox N, Griffiths C (eds) Rook’s textbook of dermatology. Blackwell Science Ltd, Oxford, pp 3.1–3.84
Koenig U, Sommergruber W, Lippens S (2005) Aberrant expression of caspase-14 in epithelial tumors. Biochem Biophys Res Commun 335:309–313
Rundhaug JE, Hawkins KA, Pavone A, Gaddis S, Kil H, Klein RD, Berton TR, McCauley E, Johnson DG, Lubet RA, Fischer SM (2005) SAGE profiling of UV-induced mouse skin squamous cell carcinomas, comparison with acute UV irradiation effects. Mol Carcinog 42(1):40–52
Yoo NJ, Soung YH, Lee SH, Jeong EG, Lee SH (2007) Mutational analysis of caspase-14 gene in common carcinomas. Pathology 39:330–333
Raymond AA, Mechin MC, Nachat R, Toulza E, Tazi-Ahnini R, Serre G, Simon M (2007) Nine procaspases are expressed in normal human epidermis, but only caspase-14 is fully processed. Br J Dermatol 156(3):420–427
Walsh DS, Borke JL, Singh BB, Do NN, Hsu SD, Balagon MV, Abalos RM (2005) Psoriasis is characterized by altered epidermal expression of caspase 14, a novel regulator of keratinocyte terminal differentiation and barrier formation. J Dermatol Sci 37:61–63
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714
Vanlangenakker N, Vanden Berghe T, Vandenabeele P (2012) Many stimuli pull the necrotic trigger, an overview. Cell Death Differ 19:75–86
Vanden Berghe T, Linkermann A, Jouan-Lanhouet S, Walczak H, Vandenabeele P (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15:135–147
Tenev T, Bianchi K, Darding M, Broemer M, Langlais C, Wallberg F, Zachariou A, Lopez J, MacFarlane M, Cain K, Meier P (2011) The ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol Cell 43:432–448
Ofengeim D, Yuan J (2013) Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol 14:727–736
Rickard JA, O’Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H, Hall C (2014) RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157:1175–1188
Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321
Takahashi N, Vereecke L, Bertrand MJ, Duprez L, Berger SB, Divert T, Gonçalves A, Sze M, Gilbert B, Kourula S, Goossens V (2014) RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513:95–99
Dannappel M, Vlantis K, Kumari S, Polykratis A, Kim C, Wachsmuth L, Eftychi C, Lin J, Corona T, Hermance N, Zelic M (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513:90–94
Monack DM, Raupach B, Hromockyj AE, Falkow S (1996) Salmonella typhimurium invasion induces apoptosis in infected macrophages. Proc Natl Acad Sci USA 93:9833–9838
Zychlinsky A, Prevost MC, Sansonetti PJ (1992) Shigella flexneri induces apoptosis in infected macrophages. Nature 358:167–169
Cookson BT, Brennan MA (2001) Pro-inflammatory programmed cell death. Trends Microbiol 9:113–114
Brennan MA, Cookson BT (2000) Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 38:31–40
Miao EA, Rajan JV, Aderem A (2011) Caspase-1-induced pyroptotic cell death. Immunol Rev 243:206–214
Bergsbaken T, Fink SL, Cookson BT (2009) Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7:99–109
Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, Warren SE, Wewers MD, Aderem A (2010) Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 11:1136–1142
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741–752
Denton D, Nicolson S, Kumar S (2012) Cell death by autophagy: facts and apparent artefacts. Cell Death Differ 19:87–95
Cho DH, Jo YK, Hwang JJ, Lee YM, Roh SA, Kim JC (2009) Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells. Cancer Lett 274:95–100
Zhu Y, Zhao L, Liu L, Gao P, Tian W, Wang X, Jin H, Xu H, Chen Q (2010) Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein Cell 1:468–477
Norman JM, Cohen GM, Bampton ET (2010) The in vitro cleavage of the hAtg proteins by cell death proteases. Autophagy 6:1042–1056
Oral O, Oz-Arslan D, Itah Z, Naghavi A, Deveci R, Karacali S, Gozuacik D (2012) Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death. Apoptosis 17:810–820
DeVorkin L, Gorski SM (2014) A mitochondrial-associated link between an effector caspase and autophagic flux. Autophagy 10:1866–1867
Tiwari M, Sharma LK, Vanegas D, Callaway DA, Bai Y, Lechleiter JD, Herman B (2014) A nonapoptotic role for CASP2/caspase 2: modulation of autophagy. Autophagy 10:1054–1070
Pagliarini V, Wirawan E, Romagnoli A, Ciccosanti F, Lisi G, Lippens S, Cecconi F, Fimia GM, Vandenabeele P, Corazzari M, Piacentini M (2012) Proteolysis of Ambra1 during apoptosis has a role in the inhibition of the autophagic pro-survival response. Cell Death Differ 19:1495–1504
Betin VM, Lane JD (2009) Atg4D at the interface between autophagy and apoptosis. Autophagy 5:1057–1059
Juo P, Kuo CJ, Yuan J, Blenis J (1998) Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol 8:1001–1008
Chen NJ, Chio II, Lin WJ, Duncan G, Chau H, Katz D, Huang HL, Pike KA, Hao Z, Su YW, Yamamoto K (2008) Beyond tumor necrosis factor receptor: TRADD signaling in tolllike receptors. Proc Natl Acad Sci 105:12429–12434
Samraj AK, Keil E, Ueffing N, Schulze-Osthoff K, Schmitz I (2006) Loss of caspase-9 provides genetic evidence for the type I/II concept of CD95-mediated apoptosis. J Biol Chem 281:29652–29659
Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DC, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A (2009) XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 460:1035–1039
Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK (2009) Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459:428–432
Brenner D, Mak TW (2009) Mitochondrial cell death effectors. Curr Opin Cell Biol 21:871–877
Shiozaki EN, Chai J, Shi Y (2002) Oligomerization and activation of caspase-9, induced by Apaf-1 CARD. Proc Natl Acad Sci 99:4197–4202
Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW (2002) Three-dimensional structure of the apoptosome: Implications for assembly, procaspase-9 binding, and activation. Mol Cell 9:423–432
Cain K, Bratton SB, Cohen GM (2002) The Apaf-1 apoptosome: a large caspase-activating complex. Biochimie 84:203–214
Yeh WC, Itie A, Elia AJ, Ng M, Shu HB, Wakeham A, Mirtsos C, Suzuki N, Bonnard M, Goeddel DV, Mak TW (2000) Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12:633–642
Hao Z, Duncan GS, Chang CC, Elia A, Fang M, Wakeham A, Okada H, Calzascia T, Jang Y, You-Ten A, Yeh WC (2005) Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis. Cell 121:579–591
Madden SD, Cotter TG (2008) Cell death in brain development and degeneration: Control of caspase expression may be key! Mol Neurobiol 37:1–6
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384:368–372
Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrachM KhooW, Kaufman SA, Senaldi G (1998) Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev 12:806–819
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:739–750
Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94:727–737
Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668
Kuida K, Lippke JA, Ku G, HardingMW LDJ, Su MS, Flavell RA (1995) Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science 267:2000–2003
Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A, Varmuza S, Latham KE, Flaws JA, Salter JC, Hara H (1998) Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 12:1304–1314
Zheng TS, Hunot S, Kuida K, Momoi T, Srinivasan A, Nicholson DW, Lazebnik Y, Flavell RA (2000) Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nat Med 6:1241–1247
Troy CM, Rabacchi SA, Hohl JB, Angelastro JM, Greene LA, Shelanski ML (2001) Death in the balance: alternative participation of the caspase-2 and -9 pathways in neuronal death induced by nerve growth factor deprivation. J Neurosci 21:5007–5016
Liu F, McCullough LD (2011) Middle cerebral artery occlusion model in rodents: methods and potential pitfalls. J Biomed Biotechnol 2011:464701
Akpan N, Serrano-Saiz E, Zacharia BE, Otten ML, Ducruet AF, Snipas SJ, Liu W, Velloza J, Cohen G, Sosunov SA, Frey WH (2011) Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J Neuroscience 31:8894–8904
Shi Y (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 9(3):459–470
Wang J, Zheng L, Lobito A, Chan FK, Dale J, Sneller M, Yao X, Puck JM, Straus SE, Lenardo MJ (1999) Inherited human Caspase 10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98(1):47–58
Earnshaw WC, Martins LM, Kaufmann SH (1999) Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 68(1):383–424
Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y (2001) Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding. Cell 107(3):399–407
Riedl SJ, Fuentes-Prior P, Renatus M, Kairies N, Krapp S, Huber R, Savesen GS, Bode W (2001) Structural basis for the activation of human procaspase-7. Proc Natl Acad Sci USA 98:14790–14795
Srinivasula SM, Ahmad M, MacFarlane M, Luo Z, Huang Z, Fernandes-Alnemri T, Alnemri ES (1998) Generation of constitutively active recombinant caspase-3 and -6 by rearrangement of their subunits. J Biol Chem 273:10107–10111
Stennicke HR, Deveraux QL, Humke EW, Reed JC, Dixit VM, Salvesen GS (1999) Caspase-9 can be activated without proteolytic processing. J Biol Chem 274:8359–8362
Huang HK, Joazeiro CAP, Bonfoco E, Kamada S, Leverson JD, Hunter T (2000) The inhibitor of apoptosis, cIAP2, functions as a ubiquitin-protein ligase and promotes in vitro monoubiquitination of caspase 3 and 7. J Biol Chem 275:26661–26664
Suzuki Y, Nakabayashi Y, Takahashi R (2001) Ubiquitin- protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti- apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA 98:8662–8667
Deveraux QL, Reed JC (1999) IAP family proteins- suppressors of apoptosis. Genes Dev 13:239–252
Hay BA (2000) Understanding IAP function and regulation: a view from Drosophila. Cell Death Differ 7:1045–1056
Ashhab Y, Alian A, Polliack A, Panet A, Yehuda DB (2001) Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett 495:56–60
Kasof GM, Gomes BC (2001) Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 276:3238–3246
Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM (2000) ML-IAP, a novel inhibitor of apoptosis that is preferenintially expressed in human melanomas. Curr Biol 10:1359–1366
Fesik SW, Shi Y (2001) Controlling caspases. Science 294:1477–1478
Shi Y (2001) A structural view of mitochondria-mediated apoptosis. Nat Struct Biol 8:394–401
Sun C, Cai M, Gunasekera AH, Meadows RP, Wang H, Chen J, Zhang H, Wu W, Xu N, Ng SC, Fesik SW (1999) NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 401:818–822
Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC (1998) Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396:580–584
Altieri DC (2001) Cytokenesis, apoptosis and survivin: three for tango? Cell Death Differ 8:4–5
Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H (2001) Structural basis of caspase inhibition by XIAP: differential roles of the Linker versus the BIR domain. Cell 104:781–790
Miller LK (1999) An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol 9:323–328
Bump NJ, Hackett M, Hugunin M, Seshagiri S, Brady K, Chen P, Ferenz C, Franklin S, Ghayur T, Li P (1995) Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35. Science 269:1885–1888
Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ, Salvesen GS (1998) Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/p35 complex. Biochem 37:10757–10765
Xu G, Cirilli M, Huang Y, Rich RL, Myszka DG, Wu H (2001) Covalent inhibition revealed by the crystal structure of the caspase-8/p35 complex. Nature 410:494–497
Du C, Fang M, Li Y, Wang X (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation during apoptosis. Cell 102:33–42
Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, Moritz RL, Simpson RJ, Vaux DL (2000) Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102:43–53
Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y (2000) Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 406:855–862
Srinivasula SM, Datta P, Fan XJ, Fernandes-Alnemri T, Huang Z, Alnemri ES (2000) Molecular determinants of the caspase- promoting activity of Smac/DIABLO and its role in the death receptor pathway. J Biol Chem 275:36152–36157
Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y (2000) Structural basis of IAP recognition by Smac/DIABLO. Nature 408:1008–1012
Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T, Herrmann J, Wu JC, Fesik SW (2000) Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 408:1004–1008
Christich A, Kauppila S, Chen P, Sogame N, Abrams JM (2002) The damage responsive Drosophila gene Sickle encodes a novel IAP binding protein similar to but distinct from Reaper, Grim and Hid. Curr Biol 12:137–140
Srinivasula SM, Datta P, Kobayashi M, Fujioka M, Wu JW, Hedge R, Zhang Z, Mukattash R, Fernandes-Alnemri T, Shi Y, Jaynes JB (2002) Sickle, a novel Drosophila death gene in the reaper/ hid/grim region encodes an IAP-inhibitory protein. Curr Biol 12:125–130
Wing JP, Karres J, Ogdahl JL, Zhou L, Schwartz LM, Nambu JR (2002) Drosophila sickle is a novel grim-reaper cell death activator. Curr Biol 12:131–135
Wu JW, Cocina AE, Chai J, Hay BA, Shi Y (2001) Structural analysis of a functional DIAP1 fragment bound to Grim and Hid peptides. Mol Cell 8:95–104
Hedge R, Srinivasula SM, Wassell R, Mukattash R, Cilenti L, Zhang Z, DuBois G, Lazebnik Y, Zervos AS, Fernandes-Alnemri T, Alnemri ES (2002) Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts IAP-caspase interaction. J Biol Chem 277:432–438
Martin LM, Iaccarino I, Tenev T, Gschmeissner S, Totty NF, Lemoine NR, Savopoulos J, Gray CW, Creasy CL, Dingwall C, Downward J (2002) The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a Reaper-like motif. J Biol Chem 277:439–444
Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621
van Loo G, van Gurp M, Depuydt B, Srinivasula SM, Rodriguez I, Alnemri ES, Gevaert K, Vandekerckhove J, Declercq W, Vandenabeele P (2002) The serine protease Omi/HtrA2 is released from mitochondria during apoptosis. Omi interacts with caspase inhibitor XIAP and induces enhanced caspase activity. Cell Death Differ 9:20–26
Verhagen AM, Silke J, Ekert PG, Pakusch M, Kaufmann H, Connolly LM, Day CL, Tikoo A, Burke R, Wrobel C, Moritz RL (2002) HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J Biol Chem 277:445–454
Gray CW, Ward RV, Karran E, Turconi S, Rowles A, Viglienghi D, Southan C, Barton A, Fantom KG, West A, Savopoulos J (2000) Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response. Eur J Biochem 267:5699–5710
Harris BZ, Lim WA (2001) Mechanism and role of PDZ domains in signaling complex assembly. J Cell Sci 114:3219–3231
Srinivasula SM, Saleh A, Hedge R, Datta P, Shiozaki E, Chai J, Robbins PD, Fernandes-Alnemri T, Shi Y, Alnemri ES (2001) A conserved XIAP-interaction motif in caspase-9 and Smac/ DIABLO mediates opposing effects on caspase activity and apoptosis. Nature 409:112–116
Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y (2001) Structural basis of caspase-7 inhibiton by XIAP. Cell 104:769–780
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MKM conceived the original idea and designed the outlines of the study. GS and MKM wrote the draft of the manuscript and prepared the figures for the manuscript. GS, DS, PK, and MKM revised and improved the manuscript. All authors have read and approved the final manuscript.
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Sahoo, G., Samal, D., Khandayataray, P. et al. A Review on Caspases: Key Regulators of Biological Activities and Apoptosis. Mol Neurobiol 60, 5805–5837 (2023). https://doi.org/10.1007/s12035-023-03433-5
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DOI: https://doi.org/10.1007/s12035-023-03433-5