Human E3 ubiquitin ligases: accelerators and brakes for SARS-CoV-2 infection

Abstract

E3 ubiquitin ligases regulate the composition of the proteome. These enzymes mono- or poly-ubiquitinate their substrates, directly altering protein function or targeting proteins for degradation by the proteasome. In this review, we discuss the opposing roles of human E3 ligases as effectors and targets in the evolutionary battle between host and pathogen, specifically in the context of SARS-CoV-2 infection. Through complex effects on transcription, translation, and protein trafficking, human E3 ligases can either attenuate SARS-CoV-2 infection or become vulnerabilities that are exploited by the virus to suppress the host's antiviral defenses. For example, the human E3 ligase RNF185 regulates the stability of SARS-CoV-2 envelope protein through the ubiquitin-proteasome pathway, and depletion of RNF185 significantly increases SARS-CoV-2 viral titer (iScience (2023) 26, 106601). We highlight recent advances that identify functions for numerous human E3 ligases in the SARS-CoV-2 life cycle and we assess their potential as novel antiviral agents.