title: A novel post-transcriptional role for ubiquitin in the differential regulation of MHC class I allotypes.
abstract: By providing ligands for Cytotoxic T-Lymphocytes (CTL) as well as Natural Killer (NK) cells, the HLA-A/B/C MHC class I molecules (MHC-I) play a central role in both innate and adaptive immunity. In addition to CTL-mediated recognition of MHC-peptide complexes, cell surface expression of MHC-I is closely monitored by NK cells, whose killer-cell immunoglobulin-like receptors encode activatory and inhibitory receptors with specificity for MHC-I. How the cell surface expression of MHC-I is tightly controlled is not well understood. In a functional siRNA ubiquitome screen to identify E3 ligases involved in MHC-I regulation we recently found that MEX-3C, a novel RNA-binding ubiquitin E3 ligase, is responsible for the post-transcriptional, HLA-A allotype-specific regulation of MHC-I. MEX-3C expression is increased upon NK cell activation and modulates the threshold of killing by these cells. We find that MEX-3C binds the 3'-untranslated region of HLA-A2 mRNA, inducing its RING-dependent degradation. The RING domain of MEX-3C is not required for HLA-A2 cell surface downregulation, but regulates the degradation of HLA-A2 mRNA. We have therefore uncovered a novel post-transcriptional pathway for regulation of HLA-A allotypes and provide a direct link between ubiquitination and mRNA decay.
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Florencia
authors.initials: F
authors.lastname: Cano
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D006680:HLA Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007126:Immunoglobulin Allotypes; D007694:Killer Cells, Natural / Q000276:immunology; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007126:Immunoglobulin Allotypes; C515359:MEX3C protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D025801:Ubiquitin