Skip to main content

Advertisement

SpringerLink
Log in

Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

Proteases, sharp yet unforgivable tools of every cell, require tight regulation to ensure specific non-aberrant cleavages. The relatively recent discovered class of intramembrane proteases has gained increasing interest due to their involvement in important signaling pathways linking them to diseases including Alzheimer’s disease and cancer. Despite tremendous efforts, their regulatory mechanisms have only started to unravel. There is evidence that the membrane composition itself can regulate intramembrane protease activity and specificity. In this review, we highlight the work on γ-secretase and rhomboid proteases and summarize several studies as to how different lipids impact on enzymatic activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Acx H, Chavez-Gutierrez L, Serneels L, Lismont S, Benurwar M, Elad N, De Strooper B (2014) Signature amyloid beta profiles are produced by different gamma-secretase complexes. J Biol Chem 289(7):4346–4355

    Article  PubMed  CAS  Google Scholar 

  • Adrain C, Zettl M, Christova Y, Taylor N, Freeman M (2012) Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335(6065):225–228

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ayciriex S, Gerber H, Osuna GM, Chami M, Stahlberg H, Shevchenko A, Fraering PC (2016) The lipidome associated with the gamma-secretase complex is required for its integrity and activity. Biochem J 473(3):321–334

    Article  PubMed  CAS  Google Scholar 

  • Bai G, Pfaff SL (2011) Protease regulation: the Yin and Yang of neural development and disease. Neuron 72(1):9–21

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR (2012) The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science 336(6085):1168–1171

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47(36):9428–9446

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Beisner DR, Langerak P, Parker AE, Dahlberg C, Otero FJ, Sutton SE, Poirot L, Barnes W, Young MA, Niessen S, Wiltshire T, Bodendorf U, Martoglio B, Cravatt B, Cooke MP (2013) The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. J Exp Med 210(1):23–30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ben-Shem A, Fass D, Bibi E (2007) Structural basis for intramembrane proteolysis by rhomboid serine proteases. Proc Natl Acad Sci USA 104(2):462–466

    Article  PubMed  CAS  Google Scholar 

  • Bergbold N, Lemberg MK (2013) Emerging role of rhomboid family proteins in mammalian biology and disease. Biochim Biophys Acta 1828(12):2840–2848

    Article  PubMed  CAS  Google Scholar 

  • Bergmann H, Yabas M, Short A, Miosge L, Barthel N, Teh CE, Roots CM, Bull KR, Jeelall Y, Horikawa K, Whittle B, Balakishnan B, Sjollema G, Bertram EM, Mackay F, Rimmer AJ, Cornall RJ, Field MA, Andrews TD, Goodnow CC, Enders A (2013) B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8-dendritic cells require the intramembrane endopeptidase SPPL2A. J Exp Med 210(1):31–40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boname JM, Bloor S, Wandel MP, Nathan JA, Antrobus R, Dingwell KS, Thurston TL, Smith DL, Smith JC, Randow F, Lehner PJ (2014) Cleavage by signal peptide peptidase is required for the degradation of selected tail-anchored proteins. J Cell Biol 205(6):847–862

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bondar AN, Val C, White SH (2009) Rhomboid protease dynamics and lipid interactions. Structure 17(3):395–405

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brown MS, Ye J, Rawson RB, Goldstein JL (2000) Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 100(4):391–398

    Article  PubMed  CAS  Google Scholar 

  • Cortesio CL, Lewellyn EB, Drubin DG (2015) Control of lipid organization and actin assembly during clathrin-mediated endocytosis by the cytoplasmic tail of the rhomboid protein Rbd2. Mol Biol Cell 26(8):1509–1522

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Das A, Brown MS, Anderson DD, Goldstein JL, Radhakrishnan A (2014). Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis. Elife 3:e02882

    Article  PubMed Central  CAS  Google Scholar 

  • De Strooper B, Chavez Gutierrez L (2015) Learning by failing: ideas and concepts to tackle gamma-secretases in Alzheimer’s disease and beyond. Annu Rev Pharmacol Toxicol 55:419–437

    Article  PubMed  CAS  Google Scholar 

  • Dhingra S, Kowlaski CH, Thammahong A, Beattie SR, Bultman KM, Cramer RA (2016). RbdB, a rhomboid protease critical for SREBP Activation and Virulence in Aspergillus fumigatus. mSphere 1(2)

  • Dickey S, Baker R, Cho S, Urban S (2013) Proteolysis inside the membrane is a rate-governed reaction not driven by substrate affinity. Cell 155(6):1270–1281

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dietschy JM (2009) Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol Chem 390(4):287–293

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Dusterhoft S, Kunzel U, Freeman M (2017) Rhomboid proteases in human disease: mechanisms and future prospects. Biochim Biophys Acta 1864(11 Pt B):2200–2209

    Article  PubMed  CAS  Google Scholar 

  • Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol 5(5):486–488

    Article  PubMed  CAS  Google Scholar 

  • Fleig L, Bergbold N, Sahasrabudhe P, Geiger B, Kaltak L, Lemberg MK (2012) Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins. Mol Cell 47(4):558–569

    Article  PubMed  CAS  Google Scholar 

  • Fluhrer R, Martin L, Klier B, Haug-Kroper M, Grammer G, Nuscher B, Haass C (2012) The alpha-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). J Biol Chem 287(7):5156–5163

    Article  PubMed  CAS  Google Scholar 

  • Fonteh AN, Chiang J, Cipolla M, Hale J, Diallo F, Chirino A, Arakaki X, Harrington MG (2013) Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer’s disease. J Lipid Res 54(10):2884–2897

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Foo ACY, Harvey BGR, Metz JJ, Goto NK (2015) Influence of hydrophobic mismatch on the catalytic activity of Escherichia coli GlpG rhomboid protease. Protein Sci 24(4):464–473

    Article  PubMed  CAS  Google Scholar 

  • Golde TE, Eckman CB (2001) Cholesterol modulation as an emerging strategy for the treatment of Alzheimer’s disease. Drug Discov Today 6(20):1049–1055

    Article  PubMed  CAS  Google Scholar 

  • Greene A, Grenier K, Aguileta M, Muise S, Farazifard R, Haque M, McBride H, Park D, Fon E (2012) Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment. EMBO Rep 13(4):378–385

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grimm MO, Kuchenbecker J, Grosgen S, Burg VK, Hundsdorfer B, Rothhaar TL, Friess P, de Wilde MC, Broersen LM, Penke B, Peter M, Vigh L, Grimm HS, Hartmann T (2011) Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. J Biol Chem 286(16):14028–14039

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grimm MO, Rothhaar TL, Grosgen S, Burg VK, Hundsdorfer B, Haupenthal VJ, Friess P, Kins S, Grimm HS, Hartmann T (2012) Trans fatty acids enhance amyloidogenic processing of the Alzheimer amyloid precursor protein (APP). J Nutr Biochem 23(10):1214–1223

    Article  PubMed  CAS  Google Scholar 

  • Haass C (2000). Presenilin proteins and their function during embryonic development and Alzheimer’s disease. Ernst Schering Res Found Workshop 29:57–64

    CAS  Google Scholar 

  • Haass C, Steiner H (2002) Alzheimer disease gamma-secretase: a complex story of GxGD-type presenilin proteases. Trends Cell Biol 12(12):556–562

    Article  PubMed  CAS  Google Scholar 

  • Haughey NJ, Bandaru VV, Bae M, Mattson MP (2010) Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim Biophys Acta 1801(8):878–886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He X, Huang Y, Li B, Gong CX, Schuchman EH (2010) Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 31(3):398–408

    Article  PubMed  CAS  Google Scholar 

  • Holmes O, Paturi S, Ye W, Wolfe MS, Selkoe DJ (2012) Effects of membrane lipids on the activity and processivity of purified gamma-secretase. Biochemistry 51(17):3565–3575

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hsu FF, Yeh CT, Sun YJ, Chiang MT, Lan WM, Li FA, Lee WH, Chau LY (2015) Signal peptide peptidase-mediated nuclear localization of heme oxygenase-1 promotes cancer cell proliferation and invasion independent of its enzymatic activity. Oncogene 34(18):2360–2370

    Article  PubMed  CAS  Google Scholar 

  • Hur JY, Welander H, Behbahani H, Aoki M, Franberg J, Winblad B, Frykman S, Tjernberg LO (2008) Active gamma-secretase is localized to detergent-resistant membranes in human brain. FEBS J 275(6):1174–1187

    Article  PubMed  CAS  Google Scholar 

  • Huttl S, Helfrich F, Mentrup T, Held S, Fukumori A, Steiner H, Saftig P, Fluhrer R, Schroder B (2016) Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. Biochem J 473(10):1405–1422

    Article  PubMed  CAS  Google Scholar 

  • Hwang J, Ribbens D, Raychaudhuri S, Cairns L, Gu H, Frost A, Urban S, Espenshade PJ (2016) A Golgi rhomboid protease Rbd2 recruits Cdc48 to cleave yeast SREBP. EMBO J 35(21):2332–2349

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Issuree PD, Maretzky T, McIlwain DR, Monette S, Qing X, Lang PA, Swendeman SL, Park-Min KH, Binder N, Kalliolias GD, Yarilina A, Horiuchi K, Ivashkiv LB, Mak TW, Salmon JE, Blobel CP (2013) iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. J Clin Invest 123(2):928–932

    PubMed  PubMed Central  CAS  Google Scholar 

  • Jin SM, Lazarou M, Wang C, Kane LA, Narendra DP, Youle RJ (2010) Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL. J Cell Biol 191(5):933–942

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jung JI, Ladd TB, Kukar T, Price AR, Moore BD, Koo EH, Golde TE, Felsenstein KM (2013) Steroids as gamma-secretase modulators. FASEB J 27(9):3775–3785

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jung JI, Price AR, Ladd TB, Ran Y, Park HJ, Ceballos-Diaz C, Smithson LA, Hochhaus G, Tang Y, Akula R, Ba S, Koo EH, Shapiro G, Felsenstein KM, Golde TE (2015) Cholestenoic acid, an endogenous cholesterol metabolite, is a potent gamma-secretase modulator. Mol Neurodegener 10:29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kaether C, Haass C, Steiner H (2006) Assembly, trafficking and function of gamma-secretase. Neurodegener Dis 3(4–5):275–283

    Article  PubMed  CAS  Google Scholar 

  • Kim J, Ha HJ, Kim S, Choi AR, Lee SJ, Hoe KL, Kim DU (2015) Identification of Rbd2 as a candidate protease for sterol regulatory element binding protein (SREBP) cleavage in fission yeast. Biochem Biophys Res Commun 468(4):606–610

    Article  PubMed  CAS  Google Scholar 

  • Kopan R, Ilagan M (2004) Gamma-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 5(6):499–504

    Article  PubMed  CAS  Google Scholar 

  • Kosicek M, Hecimovic S (2013) Phospholipids and Alzheimer’s disease: alterations, mechanisms and potential biomarkers. Int J Mol Sci 14(1):1310–1322

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kumar R, Juillerat-Jeanneret L, Golshayan D (2016) Notch antagonists: potential modulators of cancer and inflammatory diseases. J Med Chem 59(17):7719–7737

    Article  PubMed  CAS  Google Scholar 

  • Langosch D, Scharnagl C, Steiner H, Lemberg MK (2015) Understanding intramembrane proteolysis: from protein dynamics to reaction kinetics. Trends Biochem Sci 40(6):318–327

    Article  PubMed  CAS  Google Scholar 

  • Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck SM, Schuh E, Krumbholz M, Rubsamen H, Wanngren J, Khademi M, Olsson T, Alexander T, Hiepe F, Pfister HW, Weber F, Jenne D, Wekerle H, Hohlfeld R, Lichtenthaler SF, Meinl E (2015) gamma-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun 6:7333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lazareno-Saez C, Arutyunova E, Coquelle N, Lemieux MJ (2013) Domain swapping in the cytoplasmic domain of the Escherichia coli rhomboid protease. J Mol Biol 425(7):1127–1142

    Article  PubMed  CAS  Google Scholar 

  • Lemberg MK, Freeman M (2007) Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases. Genome Res 17(11):1634–1646

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lemieux MJ, Fischer SJ, Cherney MM, Bateman KS, James MN (2007) The crystal structure of the rhomboid peptidase from Haemophilus influenzae provides insight into intramembrane proteolysis. Proc Natl Acad Sci USA 104(3):750–754

    Article  PubMed  CAS  Google Scholar 

  • Lemkul JA, Bevan DR (2011) Lipid composition influences the release of Alzheimer’s amyloid beta-peptide from membranes. Protein Sci 20(9):1530–1545

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Levin-Allerhand JA, Lominska CE, Smith JD (2002) Increased amyloid- levels in APPSWE transgenic mice treated chronically with a physiological high-fat high-cholesterol diet. J Nutr Health Aging 6(5):315–319

    PubMed  CAS  Google Scholar 

  • Lichtenthaler SF, Haass C, Steiner H (2011) Regulated intramembrane proteolysis–lessons from amyloid precursor protein processing. J Neurochem 117(5):779–796

    Article  PubMed  CAS  Google Scholar 

  • Manolaridis I, Kulkarni K, Dodd RB, Ogasawara S, Zhang Z, Bineva G, Reilly NO, Hanrahan SJ, Thompson AJ, Cronin N, Iwata S, Barford D (2013) Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1. Nature 504(7479):301–305

    Article  PubMed  CAS  Google Scholar 

  • McCarthy AJ, Coleman-Vaughan C, McCarthy JV (2017) Regulated intramembrane proteolysis: emergent role in cell signalling pathways. Biochem Soc Trans 27:BST20170002

    Google Scholar 

  • McIlwain DR, Lang PA, Maretzky T, Hamada K, Ohishi K, Maney SK, Berger T, Murthy A, Duncan G, Xu HC, Lang KS, Haussinger D, Wakeham A, Itie-Youten A, Khokha R, Ohashi PS, Blobel CP, Mak TW (2012) iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science 335(6065):229–232

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • McQuibban G, Bulman D (2011) The PARLance of Parkinson disease. Autophagy 7(7):790–792

    Article  PubMed  Google Scholar 

  • McQuibban GA, Saurya S, Freeman M (2003) Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423(6939):537–541

    Article  PubMed  CAS  Google Scholar 

  • Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK (2011) The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 117(5):856–867

    Article  PubMed  CAS  Google Scholar 

  • Mentrup T, Fluhrer R, Schroder B (2017a) Latest emerging functions of SPP/SPPL intramembrane proteases. Eur J Cell Biol 96(5):372–382

    Article  PubMed  CAS  Google Scholar 

  • Mentrup T, Loock AC, Fluhrer R, Schroder B (2017b) Signal peptide peptidase and SPP-like proteases—possible therapeutic targets? Biochim Biophys Acta 1864(11 Pt B):2169–2182

    Article  PubMed  CAS  Google Scholar 

  • Miller LJ, Chacko R (2004) The role of cholesterol and statins in Alzheimer’s disease. Ann Pharmacother 38(1):91–98

    Article  PubMed  CAS  Google Scholar 

  • Moin SM, Urban S (2012) Membrane immersion allows rhomboid proteases to achieve specificity by reading transmembrane segment dynamics. Elife 1:e00173

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Motulsky AG (1986) The 1985 nobel prize in physiology or medicine. Science 231(4734):126–129

    Article  PubMed  CAS  Google Scholar 

  • Oliveira CC, Querido B, Sluijter M, de Groot AF, van der Zee R, Rabelink MJ, Hoeben RC, Ossendorp F, van der Burg SH, van Hall T (2013) New role of signal peptide peptidase to liberate C-terminal peptides for MHC class I presentation. J Immunol 191(8):4020–4028

    Article  PubMed  CAS  Google Scholar 

  • Olsson F, Schmidt S, Althoff V, Munter LM, Jin S, Rosqvist S, Lendahl U, Multhaup G, Lundkvist J (2014) Characterization of intermediate steps in amyloid beta (Abeta) production under near-native conditions. J Biol Chem 289(3):1540–1550

    Article  PubMed  CAS  Google Scholar 

  • Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ (2008) Direct and potent regulation of gamma-secretase by its lipid microenvironment. J Biol Chem 283(33):22529–22540

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Paetzel M, Karla A, Strynadka NCJ, Dalbey RE (2002) Signal peptidases. Chem Rev 102(12):4549–4579

    Article  PubMed  CAS  Google Scholar 

  • Paschkowsky S, Hamze M, Oestereich F, Munter LM (2016) Processing of the amyloid precursor protein family by rhomboid protease RHBDL4. J Biol Chem 291(42):21903–21912

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Petanceska SS, DeRosa S, Olm V, Diaz N, Sharma A, Thomas-Bryant T, Duff K, Pappolla M, Refolo LM (2002) Statin therapy for Alzheimer’s disease: will it work? J Mol Neurosci 19(1–2):155–161

    Article  PubMed  CAS  Google Scholar 

  • Pierrat OA, Strisovsky K, Christova Y, Large J, Ansell K, Bouloc N, Smiljanic E, Freeman M (2011) Monocyclic beta-lactams are selective, mechanism-based inhibitors of rhomboid intramembrane proteases. ACS Chem Biol 6(4):325–335

    Article  PubMed  CAS  Google Scholar 

  • Puglielli L, Tanzi RE, Kovacs DM (2003) Alzheimer’s disease: the cholesterol connection. Nat Neurosci 6(4):345–351

    Article  PubMed  CAS  Google Scholar 

  • Rawson RB (2013) The site-2 protease. Biochim Biophys Acta 1828(12):2801–2807

    Article  PubMed  CAS  Google Scholar 

  • Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM (1999) Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem 274(51):36801–36807

    Article  PubMed  CAS  Google Scholar 

  • Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, Thomas-Bryant T, Tint GS, Wang R, Mercken M, Petanceska SS, Duff KE (2001) A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer’s disease. Neurobiol Dis 8(5):890–899

    Article  PubMed  CAS  Google Scholar 

  • Riddell DR, Christie G, Hussain I, Dingwall C (2001) Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol 11(16):1288–1293

    Article  PubMed  CAS  Google Scholar 

  • Runz H, Rietdorf J, Tomic I, de Bernard M, Beyreuther K, Pepperkok R, Hartmann T (2002) of intracellular cholesterol transport alters presenilin localization and amyloid precursor protein processing in neuronal cells. J Neurosci 22(5):1679–1689

    Article  PubMed  CAS  Google Scholar 

  • Rushworth JV, Hooper NM (2010) Lipid rafts: linking Alzheimer’s amyloid-beta production, aggregation, and toxicity at neuronal membranes. Int J Alzheimers Dis 2011:603052

    PubMed  PubMed Central  Google Scholar 

  • Sato T, Dohmae N, Qi Y, Kakuda N, Misonou H, Mitsumori R, Maruyama H, Koo EH, Haass C, Takio K, Morishima-Kawashima M, Ishiura S, Ihara Y (2003) Potential link between amyloid beta-protein 42 and C-terminal fragment gamma 49–99 of beta-amyloid precursor protein. J Biol Chem 278(27):24294–24301

    Article  PubMed  CAS  Google Scholar 

  • Schneppenheim J, Dressel R, Huttl S, Lullmann-Rauch R, Engelke M, Dittmann K, Wienands J, Eskelinen EL, Hermans-Borgmeyer I, Fluhrer R, Saftig P, Schroder B (2013) The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. J Exp Med 210(1):41–58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Serneels L, Dejaegere T, Craessaerts K, Horre K, Jorissen E, Tousseyn T, Hebert S, Coolen M, Martens G, Zwijsen A, Annaert W, Hartmann D, De Strooper B (2005) Differential contribution of the three Aph1 genes to gamma-secretase activity in vivo. Proc Natl Acad Sci USA 102(5):1719–1724

    Article  PubMed  CAS  Google Scholar 

  • Sha HB, He Y, Yang L, Qi L (2011) Stressed out about obesity: IRE1 alpha-XBP1 in metabolic disorders. Trends Endocrinol Metab 22(9):374–381

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Shi G, Lee JR, Grimes DA, Racacho L, Ye D, Yang H, Ross OA, Farrer M, McQuibban GA, Bulman DE (2011) Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson’s disease. Hum Mol Genet 20(10):1966–1974

    Article  PubMed  CAS  Google Scholar 

  • Shi G, McQuibban GA (2017) The mitochondrial rhomboid protease PARL is regulated by PDK2 to integrate mitochondrial quality control and metabolism. Cell Rep 18(6):1458–1472

    Article  PubMed  CAS  Google Scholar 

  • Shirotani K, Edbauer D, Kostka M, Steiner H, Haass C (2004a) Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1. J Neurochem 89(6):1520–1527

    Article  PubMed  CAS  Google Scholar 

  • Shirotani K, Edbauer D, Prokop S, Haass C, Steiner H (2004b) Identification of distinct gamma-secretase complexes with different APH-1 variants. J Biol Chem 279(40):41340–41345

    Article  PubMed  CAS  Google Scholar 

  • Siggs OM, Grieve A, Xu H, Bambrough P, Christova Y, Freeman M (2014) Genetic interaction implicates iRhom2 in the regulation of EGF receptor signalling in mice. Biol Open 3(12):1151–1157

    Article  PubMed  PubMed Central  Google Scholar 

  • Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387(6633):569–572

    Article  PubMed  CAS  Google Scholar 

  • Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3(10):a004697

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95(11):6460–6464

    Article  PubMed  CAS  Google Scholar 

  • Strisovsky K (2016) Rhomboid protease inhibitors: emerging tools and future therapeutics. Semin Cell Dev Biol 60:52–62

    Article  PubMed  CAS  Google Scholar 

  • Strisovsky K, Sharpe HJ, Freeman M (2009) Sequence-specific intramembrane proteolysis: identification of a recognition motif in rhomboid substrates. Mol Cell 36(6):1048–1059

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y (2009) gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci 29(41):13042–13052

    Article  PubMed  CAS  Google Scholar 

  • Urano Y, Hayashi I, Isoo N, Reid PC, Shibasaki Y, Noguchi N, Tomita T, Iwatsubo T, Hamakubo T, Kodama T (2005) Association of active gamma-secretase complex with lipid rafts. J Lipid Res 46(5):904–912

    Article  PubMed  CAS  Google Scholar 

  • Urban S (2016) SnapShot: cartography of Intramembrane Proteolysis. Cell 167(7):1898–1898

    Article  PubMed  CAS  Google Scholar 

  • Urban S, Baker RP (2008) In vivo analysis reveals substrate-gating mutants of a rhomboid intramembrane protease display increased activity in living cells. Biol Chem 389(8):1107–1115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Urban S, Lee J, Freeman M (2001) Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107(2):173–182

    Article  PubMed  CAS  Google Scholar 

  • Urban S, Moin SM (2014) A subset of membrane-altering agents and gamma-secretase modulators provoke nonsubstrate cleavage by rhomboid proteases. Cell Rep 8(5):1241–1247

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Urban S, Wolfe MS (2005) Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc Natl Acad Sci USA 102(6):1883–1888

    Article  PubMed  CAS  Google Scholar 

  • Vaknin Y, Hillmann F, Iannitti R, Ben Baruch N, Sandovsky-Losica H, Shadkchan Y, Romani L, Brakhage A, Kniemeyer O, Osherov N (2016) Identification and characterization of a novel aspergillus fumigatus rhomboid family putative protease, RbdA, Involved in hypoxia sensing and virulence. Infect Immun 84(6):1866–1878

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • van Echten-Deckert G, Walter J (2012) Sphingolipids: critical players in Alzheimer’s disease. Prog Lipid Res 51(4):378–393

    Article  PubMed  CAS  Google Scholar 

  • van Meer G, Voelker DR, Feigenson GW (2008) Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol 9(2):112–124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Verhelst SHL (2017) Intramembrane proteases as drug targets. FEBS J 284(10):1489–1502

    Article  PubMed  CAS  Google Scholar 

  • Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G (2004) Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem 279(43):44945–44954

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Voss M, Kunzel U, Higel F, Kuhn PH, Colombo A, Fukumori A, Haug-Kroper M, Klier B, Grammer G, Seidl A, Schroder B, Obst R, Steiner H, Lichtenthaler SF, Haass C, Fluhrer R (2014) Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL3) regulates cellular N-glycosylation. EMBO J 33(24):2890–2905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wada S, Morishima-Kawashima M, Qi Y, Misono H, Shimada Y, Ohno-Iwashita Y, Ihara Y (2003) Gamma-secretase activity is present in rafts but is not cholesterol-dependent. Biochemistry 42(47):13977–13986

    Article  PubMed  CAS  Google Scholar 

  • Walder K, Kerr-Bayles L, Civitarese A, Jowett J, Curran J, Elliott K, Trevaskis J, Bishara N, Zimmet P, Mandarino L, Ravussin E, Blangero J, Kissebah A, Collier GR (2005) The mitochondrial rhomboid protease PSARL is a new candidate gene for type 2 diabetes. Diabetologia 48(3):459–468

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Wu F, Shi C (2013) Substitution of membrane cholesterol with beta-sitosterol promotes nonamyloidogenic cleavage of endogenous amyloid precursor protein. Neuroscience 247:227–233

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Casey PJ (2016) Protein prenylation: unique fats make their mark on biology. Nat Rev Mol Cell Biol 17(2):110–122

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Zhang Y, Ha Y (2006) Crystal structure of a rhomboid family intramembrane protease. Nature 444(7116):179–180

    Article  PubMed  CAS  Google Scholar 

  • Wasserman JD, Urban S, Freeman M (2000) A family of rhomboid-like genes: Drosophila rhomboid-1 and roughoid/rhomboid-3 cooperate to activate EGF receptor signaling. Genes Dev 14(13):1651–1663

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wells K, Farooqui AA, Liss L, Horrocks LA (1995) Neural membrane phospholipids in Alzheimer disease. Neurochem Res 20(11):1329–1333

    Article  PubMed  CAS  Google Scholar 

  • Winkler E, Kamp F, Scheuring J, Ebke A, Fukumori A, Steiner H (2012) Generation of Alzheimer disease-associated amyloid beta 42/43 peptide by gamma-secretase can be inhibited directly by modulation of membrane thickness. J Biol Chem 287(25):21326–21334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wolfe MS (2010) Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases. Biol Chem 391(8):839–847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Rahmati T, Donkor IO, Selkoe DJ (1999a) Peptidomimetic probes and molecular modeling suggest that Alzheimer’s gamma-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry 38(15):4720–4727

    Article  PubMed  CAS  Google Scholar 

  • Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ (1999b) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398(6727):513–517

    Article  PubMed  CAS  Google Scholar 

  • Wolozin B (2001) A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci USA 98(10):5371–5373

    Article  PubMed  CAS  Google Scholar 

  • Wu Z, Yan N, Feng L, Oberstein A, Yan H, Baker RP, Gu L, Jeffrey PD, Urban S, Shi Y (2006) Structural analysis of a rhomboid family intramembrane protease reveals a gating mechanism for substrate entry. Nat Struct Mol Biol 13(12):1084–1091

    Article  PubMed  CAS  Google Scholar 

  • Wust R, Maurer B, Hauser K, Woitalla D, Sharma M, Kruger R (2016) Mutation analyses and association studies to assess the role of the presenilin-associated rhomboid-like gene in Parkinson’s disease. Neurobiol Aging 39:217e213

    Article  CAS  Google Scholar 

  • Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB, Zhang W (2008) Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and Abeta production. Neurobiol Dis 29(3):422–437

    Article  PubMed  CAS  Google Scholar 

  • Yang G, Zhou R, Shi Y (2017) Cryo-EM structures of human gamma-secretase. Curr Opin Struct Biol 46:55–64

    Article  PubMed  CAS  Google Scholar 

  • Zettl H, Weggen S, Schneider P, Schneider G (2010) Exploring the chemical space of gamma-secretase modulators. Trends Pharmacol Sci 31(9):402–410

    Article  PubMed  CAS  Google Scholar 

  • Zhou Y, Moin SM, Urban S, Zhang Y (2012) An internal water-retention site in the rhomboid intramembrane protease GlpG ensures catalytic efficiency. Structure 20(7):1255–1263

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zoll S, Stanchev S, Began J, Skerle J, Lepsik M, Peclinovska L, Majer P, Strisovsky K (2014) Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate-peptide complex structures. EMBO J 33(20):2408–2421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank Sherilyn Junelle Recinto for eloquent suggestions for the manuscript.

Funding

This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN-2015-04645, the Canada Foundation of Innovation Leaders Opportunity Fund Grant 32565, Alzheimer Society of Canada Research Grant 17-02, Fonds d’innovation Pfizer-Fonds de recherche Santé Québec (FRQS) sur la maladie d’Alzheimer et les maladies apparentées 31288, and the Scottish Rite Charitable Foundation 16112.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, H3G 0B1, Canada

    Sandra Paschkowsky, Felix Oestereich & Lisa Marie Munter

Authors
  1. Sandra Paschkowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felix Oestereich
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lisa Marie Munter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lisa Marie Munter.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paschkowsky, S., Oestereich, F. & Munter, L.M. Embedded in the Membrane: How Lipids Confer Activity and Specificity to Intramembrane Proteases. J Membrane Biol 251, 369–378 (2018). https://doi.org/10.1007/s00232-017-0008-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-017-0008-5

Keywords

Search

Navigation