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  • 02Oct

    Why is it Important to Measure the Protein Stability of Interferon Regulatory Factor 5 (IRF5)?

    Proteins play a very important role in the human physiology and are often the key to therapeutic disease treatment.  However, development of new therapies can only happen if stable proteins are synthesized or used.

    Interferons perform a crucial part in the body’s defense system and are regulated by Interferon Regulatory Factors. These proteins and their associated functions can only be effective in long term treatments if they remain conformationally folded and biologically active.

    What Is IRF5?

    Interferon Regulatory Factors are proteins which regulate transcription and expression of interferons (IFNs), a family of secreted α -helical cytokines involved in the primary response against viral infection. They also control the propagation of viral antigens in our body. It has been proven that constitutive expression of interferons and activation of their signaling pathways have pivotal roles in host responses to malignant cells in the tumor microenvironment. (1)

    Interferon Regulation Factor 5 (IRF5) is a member of the interferon regulatory factor (IRF) family.  It is a latent transcription factor that is constitutively expressed in B cells, dendritic cells, and macrophages. Its activity can be further enhanced by type I IFN or DNA damage (2,5,6).  IRF5 is also involved in the induction of type I interferon and proinflammatory cytokines, which makes it a critical mediator of innate and adaptive immunity in the body (2-4).  In addition, it plays many other diverse roles which include,virus-mediated activation of interferons, modulation of cell growth, differentiation, apoptosis, and immune system activity.

    doctorThe Significance Of Measuring Protein Stability

    IRF5’s effectiveness is only assured if the protein remains stable.  Denaturation or unfolding can affect induction of type I IFNs and proinflammatory cytokines, as well as our body’s innate and adaptive immunity (7-9). More recent studies have shown that IRF5 is an autoimmune susceptibility gene associated with an increased risk of human systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome, and other autoimmune diseases (10-14). Genes knock-out studies coupled with protein analysis instruments like nanoDSF have been able to analyze protein stability in fine detail. This technology that uses tryptophan and tyrosin fluorescence to monitor protein unfolding, has demonstrated that the loss of IRF5 expression can contribute to tumorigenesis and metastasis (4,15-17).

    Additionally, IRF5 acts as a molecular switch that induces macrophage role in inflammation stimulation or inhibition, which are also involved in primary response against pathogenic infection. Some therapies inhibit IRF5 production in macrophages to treat a wide range of autoimmune diseases, while boosting IRF5 levels helps to treat immunocompromised patients. (18)

    New research continues to suggest the importance of protein stability in IRF5, as it examines the synthesis of small molecule inhibitors that could theoretically attenuate the levels of IRF5 in a cell.  This may be useful in the treatment of autoimmune diseases where deviant IRF5 expression and activation has been detected (5,19)

    1. Cheon H1, Borden EC2, Stark GR2. Interferons and their stimulated genes in the tumor microenvironment. Semin Oncol. 2014 Apr;41(2):156-73. doi: 10.1053.

    2. Barnes BJ, Moore PA, Pitha PM. 2001. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J. Biol. Chem.276: 23382–23390

    3. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T. 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434: 243–249

    4. Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, Takaoka A, Honda K, Taniguchi T. 2007.Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression.Proc. Natl. Acad. Sci. U. S. A. 104: 3402–3407

    5. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm G, Syvanen AC, Ronnblom L, Barnes BJ. 2010. Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum. 62: 562–573

    6. Rueda B, Reddy MV, Gonzalez-Gay MA, Balsa A, Pascual-Salcedo D, Petersson IF, Eimon A, Paira S, Scherbarth HR, Pons-Estel BA, Gonzalez-Escribano MF, Alarcon-Riquelme ME, Martin J. 2006. Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis. Arthritis Rheum. 54: 3815–3819

    7. Barnes BJ, Moore PA, Pitha PM. 2001. Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J. Biol. Chem.276: 23382–23390 [PubMed]

    8. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, Kano S, Honda K, Ohba Y, Mak TW, Taniguchi T. 2005. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434: 243–249 [PubMed]

    9. Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, Takaoka A, Honda K, Taniguchi T. 2007.Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression.Proc. Natl. Acad. Sci. U. S. A. 104: 3402–3407 [PMC free article] [PubMed]

    10. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm G, Syvanen AC, Ronnblom L, Barnes BJ. 2010. Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum. 62: 562–573 [PMC free article] [PubMed]

    11. Miceli-Richard C, Comets E, Loiseau P, Puechal X, Hachulla E, Mariette X. 2007. Association of an IRF5 gene functional polymorphism with Sjogren’s syndrome. Arthritis Rheum. 56: 3989–3994 [PMC free article] [PubMed]

    12. Rueda B, Reddy MV, González-Gay MA, Balsa A, Pascual-Salcedo D, Petersson IF, Eimon A, Paira S, Scherbarth HR, Pons-Estel BA, Gonzalez-Escribano MF, Alarcon-Riquelme ME, Martin J. 2006. Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis. Arthritis Rheum. 54: 3815–3819 [PubMed]

    13. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G, Jonsen A, Rantapää-Dahlqvist S, Moller B, Kere J, Koskenmies S, Widen E, Eloranta ML, Julkunen H, Kristjansdottir H, Steinsson K, Alm G, Ronnblom L, Syvanen AC. 2005. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 76: 528–537 [PMC free article] [PubMed]

    14. Sigurdsson S, Padyukov L, Kurreeman FA, Liljedahl U, Wiman AC, Alfredsson L, Toes R, Ronnelid J, Klareskog L, Huizinga TW, Alm G, Syvanen AC, Ronnblom L. 2007. Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. Arthritis Rheum. 56: 2202–2210 [PubMed]

    15. Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. 2003. Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res. 63: 6424–6431[PubMed]

    16. Mori T, Anazawa Y, Iiizumi M, Fukuda S, Nakamura Y, Arakawa H. 2002. Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53. Oncogene 21: 2914–2918 [PubMed]

    17. Bi X, Hameed M, Mirani N, Pimenta EM, Anari J, Barnes BJ. 2011. Loss of interferon regulatory factor 5 (IRF5) expression in human ductal carcinoma correlates with disease stage and contributes to metastasis. Breast Cancer Res. 13: R111 doi:10.1186/bcr3053

    18. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, Hussell T, Feldmann M, Udalova IA (January 2011). IRF5 promotes inflammatory macrophage polarization and T(H)1-T(H)17 responses. Nat Immunol. 12 (3): 231–238. PMID 21240265. doi:10.1038/ni.1990

    19. Stone RC, Feng D, Deng J, Singh S, Yang L, Fitzgerald-Bocarsly P, Eloranta ML, Ronnblom L, Barnes BJ. 2012. Interferon regulatory factor 5 activation in monocytes of systemic lupus erythematosus patients is triggered by circulating autoantigens independent of type I interferons.Arthritis Rheum. 64: 788–798

    20. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3663

    Anna L.

    It’s all about health!
    I have academic background in drugs related Chemical Technology, as well as extensive professional experience in pharma and medical companies. My main area of interest is everyday life medicine. The goal of my articles is to give people informative answers to the questions that bother them, to dispel doubts and some common misbeliefs and also to inspire everyone to keep healthy lifestyle.

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