Differential regulation of translational stress responses by herpesvirus ubiquitin deconjugases.

Abstract

The strategies adopted by viruses to counteract the potential antiviral effects of ribosomal quality control (RQC) that regulates the fidelity of protein translation, ribosome recycling, and the activation of ribosomal and integrated stress responses are poorly understood. Here, we investigated the capacity of the viral ubiquitin deconjugase (vDUB) encoded in the large tegument protein of human pathogenic herpesviruses to interfere with the triggering of RQC upon the induction of translational stress in cytosolic and endoplasmic reticulum (ER)-associated ribosomes. We found that the vDUBs encoded by Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and Kaposi sarcoma virus (KSHV) share the capacity to counteract the ubiquitination of RPS10, RPS20, and RPS3, and the UFMylation of RPL26 in cells treated with the translation elongation inhibitor anisomycin (ANS), which resulted in the rescue of model RQC and ER-RQC substrates from proteasome- and lysosome-dependent degradation, readthrough of stall-inducing mRNAs, and inhibition of ER-phagy. In contrast, while inhibiting the ubiquitination of RPS10, RPS20, and RPS3, and rescuing RQC substrates almost as efficiently as the homologs, the herpes simplex virus-1 (HSV1) encoded vDUB failed to counteract RPL26 UFMylation. Furthermore, it was unable to rescue the ER-RQC substrate or inhibit ER-phagy, nor did it promote ZAKα phosphorylation or activate the ISR. Our findings pinpoint important differences in the strategies adopted by these human viruses for regulating translational stress responses.