Post-translational modifications of coronavirus proteins: roles and function

Fung, To Sing; Liu, Ding Xiang

Other coronavirus proteins that modulate PTMs of host proteins Apart from the most well-characterized DUB/deISGylation activities of coronavirus PLPro, other coronavirus proteins have also been implicated in regulating PTMs of host proteins (Figure 7) . For example, in addition to the DUB activity encoded in the nsp3 of SARS-CoV, its SARS-unique domain (SUD) can also enhance a cellular E3 ubiquitin ligase called ring-finger and RCHY1, which leads to proteasomal degradation of p53 [197] . Cellular p53 inhibits replication of SARS-CoV and HCoV-NL63, presumably by activating genes involved in innate immunity. Thus, by targeting p53 for RCHY1-mediated ubiquitination and proteasomal degradation, the SUD of nsp3 may contribute to the pathogenesis of SARS-CoV [197] . Similarly, SARS-CoV ORF9b was found to localize to mitochondria and induce ubiquitination and proteasomal degradation of DRP1, leading to the elongation of mitochondrial. It might also hijack a ubiquitin E3 ligase called AIP4 to trigger the degradation of MAVS, TRAF3 and TRAF6, thereby significantly suppressing IFN responses [198] . On the other hand, ubiquitination of some cellular proteins is suppressed by coronavirus proteins. TRIM25 is an E3 ubiquitin ligase that associates with and activates RIG-I by mediating its ubiquitination. The N protein of SARS-CoV was found to bind to the SPRY domain of TRIM25 and inhibit TRIM25-dependent RIG-I activation, thereby suppressing the type I IFN production induced by poly(I:C) or Sendai virus [199] . Similarly, the accessory protein 6 of SARS-CoV was shown to interact with the IFN-signaling pathway-mediating protein Nmi and promote its ubiquitin-dependent proteasomal degradation, thereby potentially modulating the virus-induced innate immune response [200] .