Spatial and temporal roles of SARS-CoV PLpro -A snapshot

Abstract

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.

Keywords: ISG15; PLpro; SARS-CoV; SARS-CoV-2; p53; ubiquitin.

FIGURE 1

Roles of SARS‐CoV PL^pro. The green dotted frames labeled with bad effects on SARS‐CoV are the scenarios, which are unlikely to happen when SARS‐CoV prevails

FIGURE 2

Proposed strategy of PL^pro to bypass its contradictory roles in infected host cells according to its kinetic preference