SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1):

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Mehdi Moustaqil1, Emma Ollivier1, Hsin-Ping Chiu2

  • 1EMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, Australia.

Emerging Microbes & Infections
|December 29, 2020
PubMed

Insights

SARS-CoV-2 proteases NSP3 and NSP5 directly cleave host immune proteins IRF-3, NLRP12, and TAB1. This explains suppressed Type-I IFN and enhanced inflammation in COVID-19, with variations seen across species.

Area of Science:

  • Virology and Immunology
  • Molecular Biology
  • Host-Pathogen Interactions

Background:

  • SARS-CoV-2 replication relies on viral proteases NSP3 and NSP5 for polyprotein processing.
  • The innate immune system is crucial for controlling viral infections, but SARS-CoV-2 can evade it.
  • Understanding viral protease interactions with host proteins is key to COVID-19 pathogenesis.

Purpose of the Study:

  • To investigate novel functions of SARS-CoV-2 NSP3 and NSP5 proteases.
  • To identify host innate immune response proteins directly cleaved by these viral proteases.
  • To elucidate the molecular mechanisms underlying immune dysregulation in SARS-CoV-2 infection.

Main Methods:

  • In vitro assays to assess protease activity.
  • Identification of specific protein cleavage sites by NSP3 and NSP5.
  • Comparative sequence analysis of homologous proteins across different species.

Main Results:

  • NSP3 directly cleaves Interferon Regulatory Factor-3 (IRF-3).
  • NSP5 directly cleaves NLRP12 and TAB1 proteins.
  • Cleavage motifs and their presence/absence correlate with species-specific disease presentation.

Conclusions:

  • SARS-CoV-2 proteases actively suppress host innate immunity by cleaving key immune proteins.
  • NSP3-mediated IRF-3 cleavage contributes to blunted Type-I IFN responses.
  • NSP5-mediated cleavage of NLRP12 and TAB1 promotes cytokine production and inflammation.
Keywords:
IRF3NLRP12NSP3 (PLpro)NSP5 (3CLpro)SARS-CoV-2TAB1innate immunityprotease activity

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