Abstract
Pyrin and hematopoietic expression, interferon-inducible nature, and nuclear localization (HIN) domain family member 1 (PYHIN1), also known as IFIX, belongs to the family of pyrin proteins. This family includes structurally and functionally related mouse (e.g., p202, p203, and p204 proteins) and human (e.g., the interferon-inducible protein 16, absent in melanoma 2 protein, myeloid cell nuclear differentiation antigen, and pyrin and HIN domain family 1 or IFIX) proteins. The IFIX protein belongs to the HIN-200 family of interferon-inducible proteins that have a 200-amino acid signature motif at their C-termini. The increased expression of pyrin proteins in most cell types inhibits cell cycle control and modulates cell survival. Consistent with this role for pyrin proteins, IFIX is a potential antiviral DNA sensor that is essential for immune responses, the detection of viral DNA in the nucleus and cytoplasm, and the binding of foreign DNA via its HIN domain in a sequence non-specific manner. By promoting the ubiquitination and subsequent degradation of MDM2, IFIX acts as a tumor suppressor, thereby leading to p53/TP53 stabilization, HDAC1 regulation via the ubiquitin–proteasome pathway, and tumor-cell-specific silencing of the maspin gene. These data demonstrate that the potential molecular mechanism(s) underlying the action of the IFIX protein might be associated with the development of human diseases, such as viral infections, malignant tumors, and autoimmune diseases. This review summarizes the current insights into IFIX functions and how its regulation affects the outcomes of various human diseases.
Similar content being viewed by others
Abbreviations
- PRRs:
-
Pattern recognition receptors
- IFNs:
-
Interferons
- AIM2:
-
Absent in melanoma 2
- IFI16:
-
Interferon-inducible protein 16
- IFIX:
-
Interferon-inducible protein X
- MNDA:
-
Myeloid cell nuclear differentiation antigen
- PYHIN:
-
Pyrin and hematopoietic expression, interferon-inducible nature, and nuclear localization
- PY:
-
Pyrin
- NF-κB:
-
Nuclear factor-kappa B
- IL:
-
Interleukin
- HSV-1:
-
Herpes simplex virus 1
- STING:
-
Stimulator of IFN genes
- TBK1:
-
STING–TANK binding kinase 1
- dsDNA:
-
Double-strand DNA
- PML:
-
Promyelocytic leukemia
- NBs:
-
Nuclear bodies
- DDR:
-
DNA damage response
- TNFα:
-
Tumor necrosis factor alpha
- PYD:
-
Pyrin domain
- NLS:
-
Nuclear localization signal
- HPV:
-
Human papillomavirus
- EMT:
-
Epithelial mesenchymal transition
- SLE:
-
Systemic lupus erythematosus
- ICAM-1:
-
Intercellular adhesion molecule 1
- IFN-γ:
-
IFN-gamma
- IRF3:
-
Interferon regulatory factor 3
References
Brubaker SW, Bonham KS, Zanoni I et al (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257–290
Howard TR, Cristea IM (2020) Interrogating host antiviral environments driven by nuclear DNA sensing: a multiomic perspective. Biomolecules 10(12):E1591
Brennan K, Bowie AG (2010) Activation of host pattern recognition receptors by viruses. Curr Opin Microbiol 13(4):503–507
Diner BA, Li T, Greco TM et al (2015) The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA. Mol Syst Biol 11(1):787
Diner BA, Lum KK, Cristea IM (2015) The emerging role of nuclear viral DNA sensors. J Biol Chem 290(44):26412–26421
Fairbrother WJ, Gordon NC, Humke EW et al (2001) The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci 10(9):1911–1918
Jin T, Perry A, Smith P et al (2013) Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem 288(19):13225–13235
Li T, Chen J, Cristea IM (2013) Human cytomegalovirus tegument protein pUL83 inhibits IFI16-mediated DNA sensing for immune evasion. Cell Host Microbe 14(5):591–599
McConnell BB, Vertino PM (2004) TMS1/ASC: the cancer connection. Apoptosis 9(1):5–18
Jin T, Perry A, Jiang J et al (2012) Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36(4):561–571
Shaw N, Liu ZJ (2014) Role of the HIN domain in regulation of innate immune responses. Mol Cell Biol 34(1):2–15
Fernandes-Alnemri T, Yu JW, Datta P et al (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458(7237):509–513
Hornung V, Ablasser A, Charrel-Dennis M et al (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458(7237):514–518
Kumari P, Russo AJ, Shivcharan S et al (2020) AIM2 in health and disease: inflammasome and beyond. Immunol Rev 297(1):83–95
Mondini M, Costa S, Sponza S et al (2010) The interferon-inducible HIN-200 gene family in apoptosis and inflammation: implication for autoimmunity. Autoimmunity 43(3):226–231
Morrone SR, Wang T, Constantoulakis LM et al (2014) Cooperative assembly of IFI16 filaments on dsDNA provides insights into host defense strategy. Proc Natl Acad Sci USA 111(1):E62-71
Li T, Diner BA, Chen J et al (2012) Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16. Proc Natl Acad Sci USA 109(26):10558–10563
Orzalli MH, DeLuca NA, Knipe DM (2012) Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc Natl Acad Sci USA 109(44):E3008–E3017
Choubey D, Deka R, Ho SM (2008) Interferon-inducible IFI16 protein in human cancers and autoimmune diseases. Front Biosci 1(13):598–608
Ding Y, Wang L, Su LK et al (2004) Antitumor activity of IFIX, a novel interferon-inducible HIN-200 gene, in breast cancer. Oncogene 23(26):4556–4566
Chen Q, Sun L, Chen ZJ (2016) Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol 17(10):1142–1149
Everett RD, Chelbi-Alix MK (2007) PML and PML nuclear bodies: implications in antiviral defence. Biochimie 89(6–7):819–830
Tavalai N, Papior P, Rechter S et al (2006) Evidence for a role of the cellular ND10 protein PML in mediating intrinsic immunity against human cytomegalovirus infections. J Virol 80(16):8006–8018
Lukashchuk V, Everett RD (2010) Regulation of ICP0-null mutant herpes simplex virus type 1 infection by ND10 components ATRX and hDaxx. J Virol 84(8):4026–4040
Rai TS, Puri A, McBryan T et al (2011) Human CABIN1 is a functional member of the human HIRA/UBN1/ASF1a histone H3.3 chaperone complex. Mol Cell Biol 31(19):4107–4118
Glass M, Everett RD (2013) Components of promyelocytic leukemia nuclear bodies (ND10) act cooperatively to repress herpesvirus infection. J Virol 87(4):2174–2185
Nakad R, Schumacher B (2016) DNA damage response and immune defense: links and mechanisms. Front Genet 7:147
Haque A, Koide N, Odkhuu E et al (2014) Mouse pyrin and HIN domain family member 1 (pyhin1) protein positively regulates LPS-induced IFN-β and NO production in macrophages. Innate Immun 20(1):40–48
Massa D, Baran M, Bengoechea JA et al (2020) PYHIN1 regulates pro-inflammatory cytokine induction rather than innate immune DNA sensing in airway epithelial cells. J Biol Chem 295(14):4438–4450
Haque A, Koide N, Odkhuu E, Tsolmongyn B, Naiki Y, Komatsu T, Yoshida T, Yokochi T (2014) Mouse pyrin and HIN domain family member 1 (pyhin1) protein positively regulates LPS-induced IFN-β and NO production in macrophages. Innate Immun 20(1):40–48. https://doi.org/10.1177/1753425913481636
Kerur N, Veettil MV, Sharma-Walia N et al (2011) IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 9(5):363–375
Johnson KE, Chikoti L, Chandran B (2013) Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 87(9):5005–5018
Jakobsen MR et al (2013) IFI16 senses DNA forms of the lentiviral replication cycle and controls HIV-1 replication. Proc Natl Acad Sci USA 110(48):E4571–E4580
Doucas V, Ishov AM, Romo A et al (1996) Adenovirus replication is coupled with the dynamic properties of the PML nuclear structure. Genes Dev 10(2):196–207
Ishov AM, Maul GG (1996) The periphery of nuclear domain 10 (ND10) as site of DNA virus deposition. J Cell Biol 134(4):815–826
Ahn JH, Brignole EJ 3rd, Hayward GS (1998) Disruption of PML subnuclear domains by the acidic IE1 protein of human cytomegalovirus is mediated through interaction with PML and may modulate a RING finger-dependent cryptic transactivator function of PML. Mol Cell Biol 18(8):4899–4913
Chelbi-Alix MK, de Thé H (1999) Herpes virus induced proteasome-dependent degradation of the nuclear bodies-associated PML and Sp100 proteins. Oncogene 18(4):935–941
Adamson AL, Kenney S (2001) Epstein-barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies. J Virol 75(5):2388–2399
Everett RD, Murray J, Orr A, Preston CM (2007) Herpes simplex virus type 1 genomes are associated with ND10 nuclear substructures in quiescently infected human fibroblasts. J Virol 81(20):10991–11004
Howard TR, Crow MS, Greco TM, Lum KK, Li T, Cristea IM (2021) The DNA sensor IFIX drives proteome alterations to mobilize nuclear and cytoplasmic antiviral responses, with its acetylation acting as a localization toggle. mSystems 6(3):e0039721
Pierce AJ, Hu P, Han M, Ellis N, Jasin M (2001) Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev 15(24):3237–3242
de Jager M, Wyman C, van Gent DC, Kanaar R (2002) DNA end-binding specificity of human Rad50/Mre11 is influenced by ATP. Nucleic Acids Res 30(20):4425–4431
Bosso M, Kirchhoff F (2020) Emerging role of PYHIN proteins as antiviral restriction factors. Viruses 12(12):1464. https://doi.org/10.3390/v12121464
Connolly DJ, Bowie AG (2014) The emerging role of human PYHIN proteins in innate immunity: implications for health and disease. Biochem Pharmacol 92(3):405–414. https://doi.org/10.1016/j.bcp.2014.08.031
Atashzar MR, Daryabor G, Kabelitz D, Kalantar K (2019) Pyrin and hematopoietic interferon-inducible nuclear protein domain proteins: innate immune sensors for cytosolic and nuclear DNA. Crit Rev Immunol 39(4):275–288. https://doi.org/10.1615/CritRevImmunol.2020033114
Cubillos-Angulo JM, Arriaga MB, Melo MGM, Silva EC, Alvarado-Arnez LE, de Almeida AS, Moraes MO, Moreira ASR, Lapa E Silva JR, Fukutani KF, Sterling TR, Hawn TR, Kritski AL, Oliveira MM, Andrade BB (2020) Polymorphisms in interferon pathway genes and risk of Mycobacterium tuberculosis infection in contacts of tuberculosis cases in Brazil. Int J Infect Dis 92:21–28. https://doi.org/10.1016/j.ijid.2019.12.013
Tong Y, Song Y, Deng S (2019) Combined analysis and validation for DNA methylation and gene expression profiles associated with prostate cancer. Cancer Cell Int 4(19):50. https://doi.org/10.1186/s12935-019-0753-x
Fanis P, Gillemans N, Aghajanirefah A et al (2012) Five friends of methylated chromatin target of protein-arginine-methyltransferase[prmt]-1 (chtop), a complex linking arginine methylation to desumoylation. Mol Cell Proteom 11(11):1263–1273
Crow MS, Cristea IM (2017) Human antiviral protein IFIX suppresses viral gene expression during Herpes Simplex Virus 1 (HSV-1) infection and is counteracted by virus-induced proteasomal degradation. Mol Cell Proteomics 16(4 suppl 1):S200–S214
Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM (2000) A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol 10(15):886–895
Bosso M, Prelli Bozzo C, Hotter D et al (2020) Nuclear PYHIN proteins target the host transcription factor Sp1 thereby restricting HIV-1 in human macrophages and CD4+ T cells. PLoS Pathog 16(8):e1008752
Hiller S, Kohl A, Fiorito F et al (2003) NMR structure of the apoptosis- and inflammation-related NALP1 pyrin domain. Structure 11(10):1199–1205
Liepinsh E, Barbals R, Dahl E, Sharipo A, Staub E, Otting G (2003) The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol 332(5):1155–1163
Reed JC, Doctor K, Rojas A et al (2003) Comparative analysis of apoptosis and inflammation genes of mice and humans. Genome Res 13(6B):1376–1388
Stehlik C, Reed JC (2004) The PYRIN connection: novel players in innate immunity and inflammation. J Exp Med 200(5):551–558
Albrecht M, Choubey D, Lengauer T (2005) The HIN domain of IFI-200 proteins consists of two OB folds. Biochem Biophys Res Commun 327(3):679–687
Bochkarev A, Bochkareva E (2004) From RPA to BRCA2: lessons from single-stranded DNA binding by the OB-fold. Curr Opin Struct Biol 14(1):36–42
Theobald DL, Mitton-Fry RM, Wuttke DS (2003) Nucleic acid recognition by OB-fold proteins. Annu Rev Biophys Biomol Struct 32:115–133
Asefa B, Klarmann KD, Copeland NG, Gilbert DJ, Jenkins NA, Keller JR (2004) The interferon-inducible p200 family of proteins: a perspective on their roles in cell cycle regulation and differentiation. Blood Cells Mol Dis 32(1):155–167
Ludlow LE, Johnstone RW, Clarke CJ (2005) The HIN-200 family: more than interferon-inducible genes? Exp Cell Res 308(1):1–17
Gariglio M, Azzimonti B, Pagano M et al (2002) Immunohistochemical expression analysis of the human interferon-inducible gene IFI16, a member of the HIN200 family, not restricted to hematopoietic cells. J Interferon Cytokine Res 22(7):815–821
Raffaella R, Gioia D, De Andrea M et al (2004) The interferon-inducible IFI16 gene inhibits tube morphogenesis and proliferation of primary, but not HPV16 E6/E7-immortalized human endothelial cells. Exp Cell Res 293(2):331–345
Wei W, Clarke CJ, Somers GR et al (2003) Expression of IFI 16 in epithelial cells and lymphoid tissues. Histochem Cell Biol 119(1):45–54
Azzimonti B, Pagano M, Mondini M et al (2004) Altered patterns of the interferon-inducible gene IFI16 expression in head and neck squamous cell carcinoma: immunohistochemical study including correlation with retinoblastoma protein, human papillomavirus infection and proliferation index. Histopathology 45(6):560–572
DeYoung KL, Ray ME, Su YA et al (1997) Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15(4):453–457
Doggett KL, Briggs JA, Linton MF et al (2002) Retroviral mediated expression of the human myeloid nuclear antigen in a null cell line upregulates Dlk1 expression. J Cell Biochem 86(1):56–66
Fujiuchi N, Aglipay JA, Ohtsuka T et al (2004) Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation. J Biol Chem 279(19):20339–20344
Kulaeva OI, Draghici S, Tang L, Kraniak JM, Land SJ, Tainsky MA (2003) Epigenetic silencing of multiple interferon pathway genes after cellular immortalization. Oncogene 22(26):4118–4127
Mori Y, Yin J, Rashid A et al (2001) Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res 61(16):6046–6049
Pradhan A, Mijovic A, Mills K et al (2004) Differentially expressed genes in adult familial myelodysplastic syndromes. Leukemia 18(3):449–459
Varambally S, Dhanasekaran SM, Zhou M et al (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419(6907):624–629
Kimchi A, Resnitzky D, Ber R, Gat G (1988) Recessive genetic deregulation abrogates c-myc suppression by interferon and is implicated in oncogenesis. Mol Cell Biol 8(7):2828–2836
Johnstone RW, Trapani JA (1999) Transcription and growth regulatory functions of the HIN-200 family of proteins. Mol Cell Biol 19(9):5833–5838. https://doi.org/10.1128/mcb.19.9.5833
Choubey D (2000) P202: an interferon-inducible negative regulator of cell growth. J Biol Regul Homeost Agents 14(3):187–192
Saadatzadeh MR, Elmi AN, Pandya PH et al (2017) The role of MDM2 in promoting genome stability versus instability. Int J Mol Sci 18(10):2216. https://doi.org/10.3390/ijms18102216
Joazeiro CA, Weissman AM (2000) RING finger proteins: mediators of ubiquitin ligase activity. Cell 102(5):549–552
Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM (2000) Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53. J Biol Chem 275(12):8945–8951
Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420(1):25–27
Barak Y, Juven T, Haffner R, Oren M (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12(2):461–468
Picksley SM, Lane DP (1993) The p53-mdm2 autoregulatory feedback loop: a paradigm for the regulation of growth control by p53? BioEssays 15(10):689–690
Jones SN, Roe AE, Donehower LA, Bradley A (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378(6553):206–208
de Oca Luna RM, Wagner DS, Lozano G (1995) Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378(65):203–206
Deb SP (2003) Cell cycle regulatory functions of the human oncoprotein MDM2. Mol Cancer Res 1(14):1009–1016
Ding Y, Lee JF, Lu H, Lee MH, Yan DH (2006) Interferon-inducible protein IFIXalpha1 functions as a negative regulator of HDM2. Mol Cell Biol 26(5):1979–1996
Maass N, Biallek M, Rösel F et al (2002) Hypermethylation and histone deacetylation lead to silencing of the maspin gene in human breast cancer. Biochem Biophys Res Commun 297(1):125–128
Domann FE, Rice JC, Hendrix MJ, Futscher BW (2000) Epigenetic silencing of maspin gene expression in human breast cancers. Int J Cancer 85(6):805–810
Yamaguchi H, Ding Y, Lee JF et al (2008) Interferon-inducible protein IFIXalpha inhibits cell invasion by upregulating the metastasis suppressor maspin. Mol Carcinog 47(10):739–743
Riva G, Biolatti M, Pecorari G, Dell’Oste V, Landolfo S (2019) PYHIN proteins and HPV: role in the pathogenesis of head and neck squamous cell carcinoma. Microorganisms 8(1):14
Wang S, Li F, Fan H (2021) Interferon-inducible protein, IFIX, has tumor-suppressive effects in oral squamous cell carcinoma. Sci Rep 11(1):19593
Franke WW, Schmid E, Osborn M, Weber K (1979) Intermediate-sized filaments of human endothelial cells. J Cell Biol 81(3):570–580
Sen A, O'Malley K, Wang Z, Raj GV, Defranco DB, Hammes SR (2010) Paxillin regulates androgen- and epidermal growth factor-induced MAPK signaling and cell proliferation in prostate cancer cells. J Biol Chem 285(37):28787–28795. https://doi.org/10.1074/jbc.M110.134064
Andreoletti G, Ashton JJ, Coelho T, Willis C, Haggarty R, Gibson J, Holloway J, Batra A, Afzal NA, Beattie RM, Ennis S (2015) Exome analysis of patients with concurrent pediatric inflammatory bowel disease and autoimmune disease. Inflamm Bowel Dis 21(6):1229–1236. https://doi.org/10.1097/MIB.0000000000000381
Kantor DB, Palmer CD, Young TR, Meng Y, Gajdos ZK, Lyon H, Price AL, Pollack S, London SJ, Loehr LR, Smith LJ, Kumar R, Jacobs DR Jr, Petrini MF, O’Connor GT, White WB, Papanicolaou G, Burkart KM, Heckbert SR, Barr RG, Hirschhorn JN (2013) Replication and fine mapping of asthma-associated loci in individuals of African ancestry. Hum Genet 132(9):1039–47. https://doi.org/10.1007/s00439-013-1310-7
Kanteti R et al (2016) FAK and paxillin, two potential targets in pancreatic cancer. Oncotarget 7(21):31586–601
Mondini M, Costa S, Sponza S, Gugliesi F, Gariglio M, Landolfo S (2010) The interferon-inducible HIN-200 gene family in apoptosis and inflammation: implication for autoimmunity. Autoimmunity 43(3):226–231
Choubey D, Duan X, Dickerson E et al (2010) Interferon-inducible p200-family proteins as novel sensors of cytoplasmic DNA: role in inflammation and autoimmunity. J Interferon Cytokine Res 30(6):371–380
Kimkong I, Avihingsanon Y, Hirankarn N (2009) Expression profile of HIN200 in leukocytes and renal biopsy of SLE patients by real-time RT-PCR. Lupus 18(12):1066–1072
Choubey D, Panchanathan R (2008) Interferon-inducible Ifi200-family genes in systemic lupus erythematosus. Immunol Lett 119(1–2):32–41
Rozzo SJ, Allard JD, Choubey D et al (2001) Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity 15(3):435–443
Caposio P, Gugliesi F, Zannetti C et al (2007) A novel role of the interferon-inducible protein IFI16 as inducer of proinflammatory molecules in endothelial cells. J Biol Chem 282(46):33515–33529
Kumari P, Saha I, Narayanan A et al (2017) Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways. Cell Death Dis 8(10):e3078
Zitvogel L, Galluzzi L, Kepp O, Smyth MJ, Kroemer G (2015) Type I interferons in anticancer immunity. Nat Rev Immunol 15(7):405–414
Acknowledgements
We thank Editage (www.editage.cn) for English language editing.
Funding
This work was supported by grants from Chinese Postdoctoral Science Foundation (No: 2018M641872).
Author information
Authors and Affiliations
Contributions
SW and JB conceived the idea and wrote the manuscript.
Corresponding authors
Ethics declarations
Conflict of interest:
The authors declare no conflicts of interest.
Consent for publication:
Approved by all authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, S., Bai, J. Functions and roles of IFIX, a member of the human HIN-200 family, in human diseases. Mol Cell Biochem 477, 771–780 (2022). https://doi.org/10.1007/s11010-021-04297-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-021-04297-w