| Structural highlights
Disease
[IRF5_HUMAN] Genetic variations in IRF5 are associated with susceptibility to inflammatory bowel disease type 14 (IBD14) [MIM:612245]. IBD14 is a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints.[1] Genetic variations in IRF5 are associated with susceptibility to systemic lupus erythematosus type 10 (SLEB10) [MIM:612251]. Systemic lupus erythematosus (SLE) is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system. Genetic variations in IRF5 are a cause of susceptibility to rheumatoid arthritis (RA) [MIM:180300]. It is a systemic inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures.
Function
[IRF5_HUMAN] Transcription factor involved in the induction of interferons IFNA and INFB and inflammatory cytokines upon virus infection. Activated by TLR7 or TLR8 signaling.[2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Interferon regulatory factors (IRFs) are essential in the innate immune response and other physiological processes. Activation of these proteins in the cytoplasm is triggered by phosphorylation of serine and threonine residues in a C-terminal autoinhibitory region, which stimulates dimerization, transport into the nucleus, assembly with the coactivator CBP/p300 and initiation of transcription. The crystal structure of the transactivation domain of pseudophosphorylated human IRF5 strikingly reveals a dimer in which the bulk of intersubunit interactions involve a highly extended C-terminal region. The corresponding region has previously been shown to block CBP/p300 binding to unphosphorylated IRF3. Mutation of key interface residues supports the observed dimer as the physiologically activated state of IRF5 and IRF3. Thus, phosphorylation is likely to activate IRF5 and other family members by triggering conformational rearrangements that switch the C-terminal segment from an autoinihibitory to a dimerization role.
Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5.,Chen W, Lam SS, Srinath H, Jiang Z, Correia JJ, Schiffer CA, Fitzgerald KA, Lin K, Royer WE Jr Nat Struct Mol Biol. 2008 Nov;15(11):1213-20. Epub 2008 Oct 5. PMID:18836453[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S, Louis E, Wiman AC, Vermeire S, Rutgeerts P, Belaiche J, Franchimont D, Van Gossum A, Bours V, Syvanen AC. An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum Mol Genet. 2007 Dec 15;16(24):3008-16. Epub 2007 Sep 19. PMID:17881657 doi:10.1093/hmg/ddm259
- ↑ 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. J Biol Chem. 2001 Jun 29;276(26):23382-90. Epub 2001 Apr 12. PMID:11303025 doi:10.1074/jbc.M101216200
- ↑ 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. J Biol Chem. 2005 Apr 29;280(17):17005-12. Epub 2005 Jan 28. PMID:15695821 doi:10.1074/jbc.M412584200
- ↑ Chen W, Lam SS, Srinath H, Jiang Z, Correia JJ, Schiffer CA, Fitzgerald KA, Lin K, Royer WE Jr. Insights into interferon regulatory factor activation from the crystal structure of dimeric IRF5. Nat Struct Mol Biol. 2008 Nov;15(11):1213-20. Epub 2008 Oct 5. PMID:18836453 doi:10.1038/nsmb.1496
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