Specific Deubiquitinating Enzymes Promote Host Restriction Factors Against HIV/SIV Viruses.

Hijacking host ubiquitin pathways is essential for the replication of diverse viruses. However, the role of deubiquitinating enzymes (DUBs) in the interplay between viruses and the host is poorly characterized. Here, we demonstrate that specific DUBs are potent inhibitors of viral proteins from HIVs/simian immunodeficiency viruses (SIVs) that are involved in viral evasion of host restriction factors and viral replication. In particular, we discovered that T cell-functioning ubiquitin-specific protease 8 (USP8) is a potent and specific inhibitor of HIV-1 virion infectivity factor (Vif)-mediated apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3)G (A3G) degradation. Ectopic expression of USP8 inhibited Vif-induced A3G degradation and suppressed wild-type HIV-1 infectivity even in the presence of Vif. In addition, specific DUBs repressed Vpr-, Vpu-, and Vpx-triggered host restriction factor degradation. Our study has revealed a previously unrecognized interplay between the host’s DUBs and viral replication. Enhancing the antiviral activity of DUBs therefore represents an attractive strategy against HIVs/SIVs.

劫持宿主泛素途径对于多种病毒的复制至关重要。然而，去泛素化酶（DUBs）在病毒与宿主相互作用中的作用尚未得到充分阐明。在此，我们证明特定的DUBs是来自人类免疫缺陷病毒/猴免疫缺陷病毒（HIVs/SIVs）的病毒蛋白的有效抑制剂，这些病毒蛋白参与病毒逃避宿主限制因子和病毒复制。特别是，我们发现具有T细胞功能的泛素特异性蛋白酶8（USP8）是HIV - 1病毒体感染性因子（Vif）介导的载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3）G（A3G）降解的一种有效且特异性的抑制剂。USP8的异位表达抑制了Vif诱导的A3G降解，并且即使在存在Vif的情况下也抑制了野生型HIV - 1的感染性。此外，特定的DUBs抑制了Vpr -、Vpu - 和Vpx触发的宿主限制因子降解。我们的研究揭示了宿主的DUBs与病毒复制之间先前未被认识到的相互作用。因此，增强DUBs的抗病毒活性是一种针对HIVs/SIVs的有吸引力的策略。