A non-proteolytic role for ubiquitin in deadenylation of MHC-I mRNA by the RNA-binding E3-ligase MEX-3C.

The regulation of protein and mRNA turnover is essential for many cellular processes. We recently showed that ubiquitin--traditionally linked to protein degradation--directly regulates the degradation of mRNAs through the action of a newly identified family of RNA-binding E3 ubiquitin ligases. How ubiquitin regulates mRNA decay remains unclear. Here, we identify a new role for ubiquitin in regulating deadenylation, the initial and often rate-limiting step in mRNA degradation. MEX-3C, a canonical member of this family of RNA-binding ubiquitin ligases, associates with the cytoplasmic deadenylation complexes and ubiquitinates CNOT7(Caf1), the main catalytic subunit of the CCR4-NOT deadenylation machinery. We establish a new role for ubiquitin in regulating MHC-I mRNA deadenylation as ubiquitination of CNOT7 by MEX-3C regulates its deadenylation activity and is required for MHC-I mRNA degradation. Since neither proteasome nor lysosome inhibitors rescued MEX-3C-mediated MHC-I mRNA degradation, our findings suggest a new non-proteolytic function for ubiquitin in the regulation of mRNA decay.This work was supported by a Wellcome Trust Principal Research Fellowship to PJL (084957/Z/08/Z), by the Biotechnology and Biological Sciences Research Council ISPG BBS/E/B/000C0409. and the Cambridge Biomedical Research Centre (UK). The CIMR is in receipt of a Wellcome Trust Strategic Award.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ncomms967

Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef.

Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.This work was supported by a Wellcome Trust PRF (WT101835) to PJL and SRF (WT098049) to SJDN, the NIHR Cambridge BRC, a Wellcome Trust Strategic Award to CIMR and the Addenbrooke’s Charitable Trust. MPW is a Wellcome Trust Fellow (093966/Z/10/Z) and NJM is a Wellcome Trust Training Fellow (093964/Z/10/Z) and Raymond and Beverly Sackler student.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.chom.2015.09.00