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SARS-CoV-2 NSP6 reduces autophagosome size and affects viral replication via sigma-1 receptor

Cuiling Zhang1, Qiwei Jiang1, Zirui Liu1

  • 1Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, China.

Journal of Virology
|October 24, 2024
PubMed

Insights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) NSP6 protein disrupts autophagy by inhibiting lysosome function. Sigma-1 receptor knockout reversed these effects and resisted SARS-CoV-2 infection, suggesting it as a therapeutic target.

Area of Science:

  • Virology
  • Cellular Biology
  • Immunology

Background:

  • Autophagy is a cellular process involved in pathogen defense and replication.
  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structure protein 6 (NSP6) is implicated in modulating autophagy.
  • The precise mechanisms by which SARS-CoV-2 NSP6 affects autophagy and viral replication remain unclear.

Purpose of the Study:

  • To investigate the impact of SARS-CoV-2 NSP6 on autophagosome formation and function.
  • To elucidate the role of sigma-1 receptor (SIGMAR1) in SARS-CoV-2 infection and autophagy modulation.
  • To identify potential therapeutic targets for SARS-CoV-2 infection.

Main Methods:

  • Investigated the effect of NSP6 from wild-type and Delta SARS-CoV-2 variants on autophagosome size.
  • Examined the localization of SARS-CoV-2 NSP6 and its interaction with lysosomes.
  • Assessed the impact of SIGMAR1 knockout (KO) on SARS-CoV-2 infection and autophagy.
  • Analyzed endoplasmic reticulum (ER)-related pathways involved in NSP6-mediated autophagy inhibition.

Main Results:

  • SARS-CoV-2 NSP6 reduced autophagosome size in wild-type and Delta variants.
  • NSP6 localized to lysosomes, inhibiting autophagosome-lysosome fusion and blocking autophagy flux.
  • SIGMAR1 KO reversed NSP6-induced autophagosome abnormalities and conferred resistance to SARS-CoV-2 infection.
  • NSP6-induced autophagy inhibition may involve ER-related pathways.

Conclusions:

  • SARS-CoV-2 NSP6 impairs autophagy by disrupting autophagosome-lysosome fusion, potentially via ER-related mechanisms.
  • SIGMAR1 plays a critical role in SARS-CoV-2 pathogenesis and autophagy modulation.
  • SIGMAR1 represents a promising therapeutic target for developing novel anti-SARS-CoV-2 drugs.
Keywords:
NSP6SIGMAR1autophagosomeslysosome

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