SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

@article{Moustaqil2020SARSCoV2PC,
  title={SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts},
  author={Mehdi Moustaqil and Emmanuelle Ollivier and Hsin-Ping Chiu and Sarah van Tol and Paulina Rudolffi-Soto and Christian S. Stevens and Akshay Bhumkar and Dominic J. B. Hunter and Alexander N. Freiberg and David A. Jacques and Benhur Lee and Emma Sierecki and Yann Gambin},
  journal={bioRxiv},
  year={2020}
}
The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease… 

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References

SHOWING 1-10 OF 106 REFERENCES

Severe Acute Respiratory Syndrome Coronavirus Papain-Like Protease Ubiquitin-Like Domain and Catalytic Domain Regulate Antagonism of IRF3 and NF-κB Signaling

This study focuses on the SARS-CoV papain-like protease (PLP), which engages and antagonizes the IFN induction and NF-κB signaling pathways, and shows that the ubiquitin-like domain of PLP is necessary for pathway antagonism but not sufficient by itself to block these pathways regardless of the enzymatic activity of the protease.

SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6

The results revealed that the antagonism of SARS-CoV PLPro on TLR7-mediated innate immunity was associated with the negative regulation of TRAf3/6-TBK1-IRF3/NF-κB/AP1 signals.

p53 down-regulates SARS coronavirus replication and is targeted by the SARS-unique domain and PLpro via E3 ubiquitin ligase RCHY1

The significance of these findings is that down-regulation of p53 as a major player in antiviral innate immunity provides a long-sought explanation for delayed activities of respective genes.

Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease.

The findings indicate that MERS-CoV PLpro acts as a viral DUB and suppresses production of IFN-β by an interfering IRF3-mediated signalling pathway, in addition to recognizing and processing the CS at the N terminus of replicase polyprotein to release the non-structural proteins.

Papain-like protease 2 (PLP2) from severe acute respiratory syndrome coronavirus (SARS-CoV): expression, purification, characterization, and inhibition.

It is demonstrated, for the first time among coronaviral PLPs, that the reaction mechanism of SARS-CoV PLP2 is characteristic of papain and compatible with the involvement of the catalytic dyad (Cys)-S(-)/(His)-Im(+)H ion pair.

Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response through Disruption of STING-Mediated Signaling

A new mechanism used by CoVs is described in which CoV PLPs negatively regulate antiviral defenses by disrupting the STING-mediated IFN induction.

The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity

The results demonstrate an additional mechanism that PLpro is able to inhibit IRF3 signaling and suggest novel innate immune antagonism activities of PLpro that may contribute to SARS-CoV pathogenesis.

SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex

A novel mechanism is uncovered through which PLpro negatively regulates IRF3 activation by interaction with STING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.
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