Spatial and temporal roles of SARS‐CoV PL(pro)—A snapshot

Yan, Shaomin; Wu, Guang

SARS‐CoV and SARS‐CoV‐2 encode four structural and accessory proteins (spike, envelope, membrane and nucleocapsid proteins) and two polyproteins (pp1a and pp1ab). The polyproteins are further cleaved by 3C‐like cysteine protease (3CL(pro)) and papain‐like protease (PL(pro)) into 16 nonstructural proteins (nsps). PL(pro) is released from nsp3 through autocleavage, and then it cleaves the sites between nsp1/2, between nsp2/3 and between nsp3/4 with recognition motif of LXGG, and the sites in the C‐terminus of ubiquitin and of protein interferon‐stimulated gene 15 (ISG15) with recognition motif of RLRGG. Alone or together with SARS unique domain (SUD), PL(pro) can stabilize an E3 ubiquitin ligase, the ring‐finger, and CHY zinc‐finger domain‐containing 1 (RCHY1), through domain interaction, and thus, promote RCHY1 to ubiquitinate its target proteins including p53. However, a dilemma appears in terms of PL(pro) roles. On the one hand, the ubiquitination of p53 is good for SARS‐CoV because the ubiquitinated p53 cannot inhibit SARS‐CoV replication. On the other hand, the ubiquitination of NF‐κB inhibitor (IκBα), TNF receptor‐associated factors (TRAFs), and stimulator of interferon gene (STING), and the ISGylation of targeted proteins are bad for SARS‐CoV because these ubiquitination and ISGylation initiate the innate immune response and antiviral state. This mini‐review analyzes the dilemma and provides a snapshot on how the viral PL(pro) smartly manages its roles to avoid its simultaneously contradictory actions, which could shed lights on possible strategies to deal with SARS‐CoV‐2 infections.