title: Exon 6 variants carried on systemic lupus erythematosus (SLE) risk haplotypes modulate IRF5 function.
abstract: Interferon regulatory factor 5 (IRF5) regulates innate immune responses to viral infection. IRF5 genetic variants have been shown to be strongly associated with risk for systemic lupus erythematosus (SLE). Functional roles of IRF5 exon 6 structural variants that occur as part of a SLE risk-associated haplotype, including a 30-bp in/del (in/del-10) and a 48-bp splice-site variant (SV-16), have not been established. In this study, we used IRF5-deficient cells overexpressing human IRF5 (hIRF5) variants to investigate the roles of exon 6 in/del-10 and SV-16 in regulation of the apoptosis response, nuclear translocation, and ability to transactivate IRF5 responsive cytokines. We found that expression of IRF5 isoforms including either SV-16 or in/del-10 confers ability of IRF5 to impair the apoptotic response and correlates with reduced capacity for IRF5 nuclear translocation in MEFs after a DNA-damaging stimulus treatment. Interestingly, the presence or absence of both SV-16 and in/del-10 results in abrogation of both the anti-apoptotic and enhanced nuclear translocation effects of IRF5 expression. Only cells expressing IRF5 bearing SV-16 show increased IL-6 production upon lipopolysaccharide stimulation. MEFs expressing hIRF5 variants containing in/del-10 showed no significant difference from the control; however, cells carrying hIRF5 lacking both SV-16 and in/del-10 showed reduced IL-6 production. Our overall findings suggest that exon 6 SV-16 is more potent than in/del-10 for IRF5-driven resistance to apoptosis and promotion of cytokine production; however, in/del-10 co-expression can neutralize these effects of SV-16.
authors.affiliation: Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wen
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Ellingson
authors.forename: Chieko
authors.initials: C
authors.lastname: Kyogoku
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Peterson
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
chemical_list: D016207:Cytokines; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D020033:Protein Isoforms