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Monitoring Activation of the Antiviral Pattern Recognition Receptors RIG-I And PKR By Limited Protease Digestion and Native PAGE
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Diverse strategies utilized by coronaviruses to evade antiviral responses and suppress pyroptosis

Xinyu Fu1, Weilv Xu1, Yang Yang2

  • 1Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, China.

International Journal of Biological Macromolecules
|January 11, 2025
PubMed

Insights

Coronaviruses stabilize caspase-1 to disrupt immune signaling and pyroptosis. A PLP2 inhibitor reversed these effects, reducing viral replication and revealing a novel viral evasion strategy.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Viral infections activate inflammasomes and caspase-1.
  • Mechanisms by which viruses utilize active caspase-1 to evade host immunity are not fully understood.

Purpose of the Study:

  • To elucidate how coronaviruses (CoVs), using porcine epidemic diarrhea virus (PEDV) as a model, regulate host immune responses, specifically Interferon-I (IFN-I) signaling and pyroptosis, by manipulating active caspase-1.
  • To investigate the role of PEDV's papain-like protease PLP2 in this process and identify potential therapeutic targets.

Main Methods:

  • Utilized PEDV as a model coronavirus.
  • Investigated the deubiquitinase activity of PLP2 on caspase-1 stability.
  • Analyzed the cleavage of RIG-I by caspase-1.
  • Assessed the effect of 6-thioguanine (6TG), a PLP2 inhibitor, on IFN-I signaling and viral replication.
  • Examined the degradation of GSDMD-p30 by PLP2 and its impact on pyroptosis.
  • Compared PLP2 activity with papain-like proteases from other CoVs (PDCoV, SARS-CoV-2).
  • Investigated SARS-CoV-2 N protein-induced inflammasome activation and its effect on RIG-I.

Main Results:

  • PEDV infection stabilizes caspase-1 via PLP2 deubiquitinase activity.
  • Stabilized caspase-1 cleaves RIG-I at D189, disrupting IFN-I signaling.
  • The PLP2 inhibitor 6TG reverses IFN-I inhibition and reduces PEDV replication.
  • PLP2 degrades GSDMD-p30 by removing K27-linked ubiquitin chains, thereby restraining pyroptosis.
  • Papain-like proteases from PDCoV and SARS-CoV-2 exhibit similar GSDMD-p30 degradation activity.
  • SARS-CoV-2 N protein utilizes active caspase-1 to disrupt IFN-I signaling by cleaving RIG-I.

Conclusions:

  • CoVs employ a novel mechanism involving stabilized caspase-1 to evade host antiviral responses, including IFN-I signaling and pyroptosis.
  • PLP2 plays a critical role in stabilizing caspase-1 and inhibiting host immunity.
  • Targeting PLP2 with inhibitors like 6TG shows therapeutic potential against CoV infections.
Keywords:
Antiviral immunityCoronavirusGSDMDPapain-like proteaseType I interferon signaling

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