The Epstein Barr virus deubiquitinase BPLF1 regulates stress-induced ribosome UFMylation and ER-phagy

Abstract

Abstract The synthesis of membrane and secreted proteins is safeguarded by an Endoplasmic Reticulum-associated Ribosome Quality Control (ER-RQC) that promotes the disposal of defective translation products by the proteasome or via a lysosome-dependent pathway involving the degradation of portions of the ER by macroautophagy (ER-phagy). The UFMylation of RPL26 on ER-stalled ribosomes is essential for activating the ER-RQC and ER-phagy. Here, we report that the viral deubiquitinase (vDUB) encoded in the N-terminal domain of the EBV large tegument protein BPLF1 hinders the UFMylation of RPL26 on ribosomes that stall at the ER, promotes the stabilization of ER-RQC substrates, and inhibits ER-phagy. We found that the vDUB does not have UFM1 deconjugase activity and does not prevent the UFMylation of the ER membrane protein CYB5R3. However, it copurifies with ribosomes in sucrose gradients and abrogates a ZNF598- and LTN1-independent ubiquitination event that appears to be required for RPL26 UFMylation. Physiological levels of BPLF1 impaired RPL26 UFMylation and promoted the accumulation of lipidated LC3-II in productively EBV-infected cells, pointing to an important role of the enzyme in regulating the translation quality control that allows the efficient synthesis of viral proteins and the production of infectious virus.