Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

By Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, D. Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, M. Widera, A. Mehdipour, G. Tascher and 12 more. Nature, 2020

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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 spread1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses3–5. 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).

Subfields: Animal Science and Zoology, Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/9949face78980ea21edae47a261b0c8b67173908

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In Immunology

1. A. García‐Sastre
2. Michael S. Diamond
3. Anna Marie Pyle
4. Wenshuai Wang

In Infectious Diseases

1. Wenshuai Wang
2. Anna Marie Pyle

Citations in the corpus

• Host cell-intrinsic innate immune recognition of SARS-CoV-2 (2021, positive): “MDA5, the two most prominent RLR members, associate at the mitochondrial membrane with the shared adaptor protein MAVS and trigger a TBK1-IRF3 signaling cascade that induces a type I and III interferon (IFN) response [20,21].”
• SARS-CoV-2 Orf6 hijacks Nup98 to block STAT nuclear import and antagonize interferon signaling (2020, background): “For instance, the nonstructural protein Nsp1 of SARS-CoV was shown to decrease phosphorylation levels of STAT1 (22); the accessory proteins Orf3b and Orf6 appeared to inhibit IFN production and signaling by blocking nuclear translocation of transcription factors (20, 21); and the SARS-CoV-2 encoded ”