The RNA‐binding E3 ubiquitin ligase MEX‐3C links ubiquitination with MHC‐I mRNA degradation

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.