Differential regulation of translational stress responses by herpesvirus ubiquitin deconjugases
The strategies adopted by viruses to counteract the potential antiviral effects of the ribosomal quality control (RQC) that regulates the fidelity of protein translation, ribosome recycling, and the activation of ribosomal and integrates 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 ribosome. We found that the capacity of the vDUBs encoded by Epstein-Barr virus (EBV), Human cytomegalovirus (HCMV), and Kaposi sarcoma virus (KSHV) to counteract the ubiquitination of RPS10, RPS20, and RPS3, and the UFMylation of RPL26 in cells treated with translation elongation inhibitor anisomycin (ANS) correlated with the rescue of model RQC and ER-RQC substrates from proteasome- and lysosome-dependent degradation, promoted the readthrough of stall-inducing mRNAs, and prevented ER-phagy. In contrast, while rescuing the RQC substrate and inhibiting the ubiquitination of RPS10, RPS20, and RPS3 as almost efficiently as the homologs, the Herpes simplex virus-1 (HSV1) encoded vDUB failed to counteract RPL26 UFMylation and did not rescue the ER-RQC substrate or inhibit ER-phagy. Thus, it appears that the different lifestyles of herpesviruses may have promoted the development of distinct strategies for coping with the antiviral effect of ribosome stress responses.