title: A novel link of HLA locus to the regulation of immunity and infection: NFKBIL1 regulates alternative splicing of human immune-related genes and influenza virus M gene.
abstract: HLA locus contains immune-related genes and genetically regulates immune responses against both foreign- and self-antigens in humans. Inhibitor of κB-like protein (IκBL), encoded by HLA-linked NFKBIL1, is a protein of unknown function, while genetic variations in NFKBIL1 are known to associate with the susceptibility to inflammatory and/or autoimmune diseases. In this study, we found that IκBL suppressed exon exclusion in alternative splicing of human immune-related genes such as CD45. Yeast-two-hybrid screening and immunoprecipitation assay revealed molecular association of IκBL with CLK1, a serine/threonine and tyrosine kinase, which plays a role in the alternative splicing. Unexpectedly, we found that the regulation of alternative splicing in CD45 by IκBL was independent from the kinase activity of CLK1. On the other hand, it was demonstrated that an SR protein, ASF/SF2, bound both IκBL and CLK1 at the RNA-recognition motifs of ASF/SF2, implying a competition of IκBL and CLK1 on SR protein. In addition, IκBL was found to regulate the CLK1-dependent synthesis of M2 RNA, a splice variant of influenza A virus M gene. These observations suggest a functional involvement of IκBL in the regulation of alternative splicing in both human and viral genes, which is a novel link of HLA locus to the regulation of immunity and infection in humans.
authors: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Jianbo
authors: J
authors: An
authors: Toshiaki
authors: T
authors: Nakajima
authors: Hiroki
authors: H
authors: Shibata
authors: Takuro
authors: T
authors: Arimura
authors: Michio
authors: M
authors: Yasunami
authors: Akinori
authors: A
authors: Kimura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017398:Alternative Splicing; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006680:HLA Antigens / Q000235:genetics*; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D009980:Influenza A virus / Q000235:genetics*; D017493:Leukocyte Common Antigens / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D014763:Viral Matrix Proteins / Q000235:genetics*; D000086082:Viroporin Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006680:HLA Antigens; D000949:Histocompatibility Antigens Class II; D017493:Leukocyte Common Antigens; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D000068103:Serine-Arginine Splicing Factors; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C120111:NFKBIL1 protein, human; C066780:Clk dual-specificity kinases
keywords: ASF/SF2; Alternative splicing; CLK1; Immune-related gene; NFKBIL1