Remodeling of the Ribosomal Quality Control and Protein Translation by a Viral Ubiquitin Deconjugase

Abstract

The strategies adopted by viruses to reprogram the protein translation and quality control machineries to promote infection are poorly understood. Here, we discovered that the viral ubiquitin deconjugase (vDUB) encoded in the large tegument protein of Epstein- Barr virus (EBV) regulates ribosomal stress responses. The vDUB participates in protein complexes that include the ubiquitin ligases ZNF598 and LTN1 and the UFM1 ligase UFL1. Upon ribosomal stalling, the vDUB counteracts the ubiquitination of 40S ribosome subunits, inhibits the degradation of translation-stalled polypeptides by the proteasome, and prevents UFMylation of the 60S particle, which impairs the ER-phagy- dependent clearance of stalled products. Inhibition of the ribosome quality control activates a GCN2-dependent integrated stress response that decreases global protein translation while promoting the readthrough of stall-inducing mRNAs. The vDUB enhances viral mRNAs translation and virus release during productive infection, pointing to a pivotal role in cell reprogramming that enables virus production and underlies the pathogenesis of EBV-associated cancers and autoimmune diseases. GRAPHIC SUMMARY O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/526464v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1c7421dorg.highwire.dtl.DTLVardef@c59b8dorg.highwire.dtl.DTLVardef@1676b4eorg.highwire.dtl.DTLVardef@b5e111_HPS_FORMAT_FIGEXP M_FIG C_FIG