title: The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation.
abstract: RNA-binding E3 ubiquitin ligases were recently identified, though their function remains unclear. While studying the regulation of the MHC class I (MHC-I) pathway, we here characterize a novel role for ubiquitin in mRNA degradation. MHC-I molecules provide ligands for both cytotoxic T-lymphocytes as well as natural killer (NK) cells, and play a central role in innate and adaptive immunity. MHC-I cell-surface expression is closely monitored by NK cells, whose killer immunoglobulin-like receptors encode MHC-I-specific activatory and inhibitory receptors, implying that MHC-I expression needs to be tightly regulated. In a functional siRNA ubiquitome screen we identified MEX-3C, a novel RNA-binding ubiquitin E3 ligase, as responsible for the post-transcriptional, allotype-specific regulation of MHC-I. MEX-3C binds the 3'UTR 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 link between ubiquitination and mRNA degradation.
authors.affiliation: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Florencia
authors.initials: F
authors.lastname: Cano
authors.forename: Helen
authors.initials: H
authors.lastname: Bye
authors.forename: Lidia M
authors.initials: LM
authors.lastname: Duncan
authors.forename: Karine
authors.initials: K
authors.lastname: Buchet-Poyau
authors.forename: Marc
authors.initials: M
authors.lastname: Billaud
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wills
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D002460:Cell Line; D057809:HEK293 Cells; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D015789:HLA-A2 Antigen; C515359:MEX3C protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins