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The P132H mutation of SARS-CoV-2 NSP5 relieves its inhibition on interferon-β activation via blocking MAVS

Yuxin Zhang1, Tong-Yun Wang2, Huihui Yan1

  • 1Hunan Provincial Key Laboratory of Medical Virology and Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan University, 27 Tianma Rd, Changsha, 410082, Hunan, China.

Cellular and Molecular Life Sciences : CMLS
|July 30, 2025
PubMed

Insights

The Omicron variant

Area of Science:

  • Virology and Molecular Biology
  • Immunology
  • Epidemiology

Background:

  • The Omicron variant of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) represents a significant shift in the COVID-19 pandemic.
  • Omicron and its subvariants display reduced pathogenicity compared to previous strains, contributing to epidemic moderation.
  • The precise molecular mechanisms behind Omicron's decreased pathogenicity remain incompletely understood.

Purpose of the Study:

  • To investigate the molecular mechanism underlying the decreased pathogenicity of the SARS-CoV-2 Omicron variant.
  • To elucidate the role of the NSP5 P132H mutation in modulating viral cytopathogenicity and replication.

Main Methods:

  • Analysis of the NSP5 P132H mutation found exclusively in Omicron and its subvariants.
  • In vitro studies to assess the impact of the P132H mutation on MAVS ubiquitination and IFN-β activation.
  • In silico structural analysis to examine the interaction between mutated NSP5 and UbcH5b.

Main Results:

  • The NSP5 P132H mutation was found to solely relieve cytopathogenicity and reduce viral replication in SARS-CoV-2 infection.
  • P132H inhibits NSP5-mediated MAVS degradation by impairing K136-linked ubiquitination, thereby restoring IFN-β activation.
  • In silico analysis indicated that P132H disrupts hydrogen bonds between NSP5 and UbcH5b, crucial for MAVS ubiquitination.

Conclusions:

  • The P132H mutation in NSP5 is a key factor contributing to the reduced pathogenicity of the SARS-CoV-2 Omicron variant.
  • This mutation restores innate antiviral immunity by preventing MAVS degradation and promoting IFN-β activation.
  • The findings provide a mechanistic explanation for the observed attenuation of the Omicron variant.
Keywords:
IFN-βMAVSNSP5P132HSARS-CoV-2 variants

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