Post-translational modifications of coronavirus proteins: roles and function

Fung, To Sing; Liu, Ding Xiang

Since ubiquitination and ISGylation are critical for signaling transduction of innate immunity, the DUB and deISGylating activities of coronavirus PLPro are well characterized as antagonists of host antiviral response ( Figure 7 ) [188] . Initial studies identified SARS-CoV PLPro as a potent IFN antagonist by interacting with IRF3 and inhibiting its phosphorylation and nuclear translocation, thereby blocking type I IFN production [189] . Subsequently, it was found that SARS-CoV PLPro could also inhibit TNFα-induced NF-κB activation [190] and blocked the production of proinflammatory cytokines and chemokines in activated cells [179] . The IFN antagonist activity of coronavirus PLPro can be mediated by multiple mechanisms, which may or may not involve its protease and DUB activities [191] . PLP2 of MHV-A59 was found to directly deubiquitinate IRF3 and prevent its nuclear translocation [178] . It also deubiquitinated upstream TBK1 and reduced its kinase activity, thereby inhibiting IFN signaling [192] . PLPro of SARS-CoV was shown to remove K63-linked ubiquitin chains from TRAF3 and TRAF6, thereby suppressing the activation of TBK1 in cells treated with TLR7 agonist [193] . Alternatively, membraneanchored SARS-CoV PLPro might physically interact with the STING-TRAF3-TBK1 complex to inhibit the phosphorylation and dimerization of IRF3, thereby suppressing the STING/TBK1/IKKε-mediated activation of type I IFN [194, 195] . At last, using a constitutively active phosphor-mimetic IRF3, it was recently shown that the DUB activity of PLPro also inhibited IRF3 at a postactivation step [196] .