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Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
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Journal Article
Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
2020
Overview
The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread
1
,
2
. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses
3
–
5
. Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity.
Biochemical, structural and functional studies on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease PLpro reveal that it regulates host antiviral responses by preferentially cleaving the ubiquitin-like interferon-stimulated gene 15 protein (ISG15) and identify this protease as a potential therapeutic target for coronavirus disease 2019 (COVID-19).
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 82
/ 82/58
/ Animals
/ Coronavirus Papain-Like Proteases - antagonists & inhibitors
/ Coronavirus Papain-Like Proteases - chemistry
/ Coronavirus Papain-Like Proteases - metabolism
/ COVID-19
/ Deubiquitinating Enzymes - antagonists & inhibitors
/ Deubiquitinating Enzymes - chemistry
/ Deubiquitinating Enzymes - metabolism
/ Enzymes
/ Humanities and Social Sciences
/ Humans
/ Immunity
/ Interferon Regulatory Factor-3 - metabolism
/ Mice
/ Middle East respiratory syndrome
/ Molecular Dynamics Simulation
/ Papain
/ Protease
/ Proteins
/ Science
/ Severe acute respiratory syndrome coronavirus 2
