IRF5 explained

Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene.^[1] The IRF family is a group of transcription factors that are involved in signaling for virus responses in mammals along with regulation of certain cellular functions.^[2]

Function

IRF5 is a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Alternative splice variants encoding different isoforms exist.^[1] The regulatory and repression regions of the IRF family are mainly located in the C-terminal of the IRF.^[3]

A 2020 study showed that an adaptor protein named TASL play an important regulatory role in IRF5 activation by being phosphorylated at the pLxIS motif,^[4] drawing a similar analogy to the IRF3 activation pathway through the adaptor proteins MAVS, STING and TRIF.^[5]

Clinical significance

IRF5 acts as a molecular switch that controls whether macrophages will promote or inhibit inflammation. Blocking the production of IRF5 in macrophages may help treat a wide range of autoimmune diseases, and that boosting IRF5 levels might help treat people whose immune systems are weak, compromised, or damaged. IRF5 seems to work "either by interacting with DNA directly, or by interacting with other proteins that themselves control which genes are switched on."^[6]

Signaling

The IRF family regulates the gene expression for the interferon (IFN) response to viral infections. IRF5 is a direct transducer to interferon signaling and is activated via phosphorylation.^[7] The IRF family can also initiate the JAK/STAT signaling pathway by binding to transmembrane receptors that activate JAK.^[8] IRFs, IFNs, and the JAK/STAT signaling pathway work together to fight viral infections in mammals through specific signals.^[9]

See also

• Interferon regulatory factors

References

Further reading

• Pitha PM, Au WC, Lowther W, Juang YT, Schafer SL, Burysek L, Hiscott J, Moore PA . Role of the interferon regulatory factors (IRFs) in virus-mediated signaling and regulation of cell growth . Biochimie . 80 . 8–9 . 651–658 . 1999 . 9865487 . 10.1016/S0300-9084(99)80018-2 . free .
• Barnes B, Lubyova B, Pitha PM . On the role of IRF in host defense . Journal of Interferon & Cytokine Research . 22 . 1 . 59–71 . January 2002 . 11846976 . 10.1089/107999002753452665 .
• Barnes BJ, Moore PA, Pitha PM . Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes . The Journal of Biological Chemistry . 276 . 26 . 23382–23390 . June 2001 . 11303025 . 10.1074/jbc.M101216200 . free .
• Nehyba J, Hrdlicková R, Burnside J, Bose HR . A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein . Molecular and Cellular Biology . 22 . 11 . 3942–3957 . June 2002 . 11997525 . 133824 . 10.1128/MCB.22.11.3942-3957.2002 .
• Barnes BJ, Kellum MJ, Field AE, Pitha PM . Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes . Molecular and Cellular Biology . 22 . 16 . 5721–5740 . August 2002 . 12138184 . 133975 . 10.1128/MCB.22.16.5721-5740.2002 .
• Barnes BJ, Field AE, Pitha-Rowe PM . Virus-induced heterodimer formation between IRF-5 and IRF-7 modulates assembly of the IFNA enhanceosome in vivo and transcriptional activity of IFNA genes . The Journal of Biological Chemistry . 278 . 19 . 16630–16641 . May 2003 . 12600985 . 10.1074/jbc.M212609200 . free .
• Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM . Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death . Cancer Research . 63 . 19 . 6424–6431 . October 2003 . 14559832 .
• Barnes BJ, Richards J, Mancl M, Hanash S, Beretta L, Pitha PM . Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection . The Journal of Biological Chemistry . 279 . 43 . 45194–45207 . October 2004 . 15308637 . 10.1074/jbc.M400726200 . free .
• Lin R, Yang L, Arguello M, Penafuerte C, Hiscott J . A CRM1-dependent nuclear export pathway is involved in the regulation of IRF-5 subcellular localization . The Journal of Biological Chemistry . 280 . 4 . 3088–3095 . January 2005 . 15556946 . 10.1074/jbc.M408452200 . free .
• Sigurdsson S, Nordmark G, Göring HH, Lindroos K, Wiman AC, Sturfelt G, Jönsen A, Rantapää-Dahlqvist S, Möller B, Kere J, Koskenmies S, Widén E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, Rönnblom L, Syvänen AC . Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus . American Journal of Human Genetics . 76 . 3 . 528–537 . March 2005 . 15657875 . 1196404 . 10.1086/428480 .
• Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T . Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors . Nature . 434 . 7030 . 243–249 . March 2005 . 15665823 . 10.1038/nature03308 . 667829 . 2005Natur.434..243T .
• Schoenemeyer A, Barnes BJ, Mancl ME, Latz E, Goutagny N, Pitha PM, Fitzgerald KA, Golenbock DT . The interferon regulatory factor, IRF5, is a central mediator of toll-like receptor 7 signaling . The Journal of Biological Chemistry . 280 . 17 . 17005–17012 . April 2005 . 15695821 . 10.1074/jbc.M412584200 . free .
• Mancl ME, Hu G, Sangster-Guity N, Olshalsky SL, Hoops K, Fitzgerald-Bocarsly P, Pitha PM, Pinder K, Barnes BJ . Two discrete promoters regulate the alternatively spliced human interferon regulatory factor-5 isoforms. Multiple isoforms with distinct cell type-specific expression, localization, regulation, and function . The Journal of Biological Chemistry . 280 . 22 . 21078–21090 . June 2005 . 15805103 . 10.1074/jbc.M500543200 . free .
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–1178 . October 2005 . 16189514 . 10.1038/nature04209 . 4427026 . 2005Natur.437.1173R .
• Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, Ortmann WA, Koeuth T, González Escribano MF, Pons-Estel B, Petri M, Daly M, Gregersen PK, Martín J, Altshuler D, Behrens TW, Alarcón-Riquelme ME . A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus . Nature Genetics . 38 . 5 . 550–555 . May 2006 . 16642019 . 10.1038/ng1782 . 21426281 .

Notes and References

1. Web site: Entrez Gene: IRF5 interferon regulatory factor 5.
2. Negishi H, Taniguchi T, Yanai H . The Interferon (IFN) Class of Cytokines and the IFN Regulatory Factor (IRF) Transcription Factor Family . Cold Spring Harbor Perspectives in Biology . 10 . 11 . a028423 . November 2018 . 28963109 . 6211389 . 10.1101/cshperspect.a028423 . free .
3. Chistiakov DA, Myasoedova VA, Revin VV, Orekhov AN, Bobryshev YV . The impact of interferon-regulatory factors to macrophage differentiation and polarization into M1 and M2 . Immunobiology . 223 . 1 . 101–111 . January 2018 . 29032836 . 10.1016/j.imbio.2017.10.005 .
4. Heinz LX, Lee J, Kapoor U, Kartnig F, Sedlyarov V, Papakostas K, César-Razquin A, Essletzbichler P, Goldmann U, Stefanovic A, Bigenzahn JW, Scorzoni S, Pizzagalli MD, Bensimon A, Müller AC, King FJ, Li J, Girardi E, Mbow ML, Whitehurst CE, Rebsamen M, Superti-Furga G . TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9 . Nature . 581 . 7808 . 316–322 . May 2020 . 32433612 . 7610944 . 10.1038/s41586-020-2282-0 . 218625265 . 2020Natur.581..316H .
5. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV, Chen ZJ . Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation . Science . 347 . 6227 . aaa2630 . March 2015 . 25636800 . 10.1126/science.aaa2630 . free .
6. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA . IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses . Nature Immunology . 12 . 3 . 231–238 . March 2011 . 21240265 . 10.1038/ni.1990 . 13730047 .
7. Barnes B, Lubyova B, Pitha PM . On the role of IRF in host defense . Journal of Interferon & Cytokine Research . 22 . 1 . 59–71 . January 2002 . 11846976 . 10.1089/107999002753452665 .
8. Bousoik E, Montazeri Aliabadi H . "Do We Know Jack" About JAK? A Closer Look at JAK/STAT Signaling Pathway . English . Frontiers in Oncology . 8 . 287 . 2018 . 30109213 . 6079274 . 10.3389/fonc.2018.00287 . free .
9. Chiang HS, Liu HM . The Molecular Basis of Viral Inhibition of IRF- and STAT-Dependent Immune Responses . English . Frontiers in Immunology . 9 . 3086 . 2019 . 30671058 . 6332930 . 10.3389/fimmu.2018.03086 . free .