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NSP6 of SARS-CoV-2 Dually Regulates Autophagic-Lysosomal Degradation

Haijiao Zhang1, Jianying Chang1, Ren Sheng1

  • 1College of Life and Health Science, Northeastern University, Shenyang 110819, China.

International Journal of Molecular Sciences
|May 7, 2025
PubMed

Insights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Non-structural protein 6 (NSP6) regulates autophagy initiation and blocks degradation. A specific NSP6 variant (L37F) impairs this blockage, potentially influencing COVID-19 pathogenesis.

Area of Science:

  • Virology
  • Cellular Biology
  • Immunology

Background:

  • The COVID-19 pandemic, caused by SARS-CoV-2, necessitates understanding viral pathogenesis mechanisms.
  • Autophagy, a cellular degradation process, is implicated in viral infections.

Purpose of the Study:

  • To elucidate the role of SARS-CoV-2 Non-structural protein 6 (NSP6) in regulating host cell autophagy.
  • To investigate the impact of an NSP6 single nucleotide polymorphism (SNP) on autophagy pathways.

Main Methods:

  • Investigated the interaction of SARS-CoV-2 NSP6 with autophagy-related proteins, specifically Beclin1.
  • Assessed the effect of NSP6 on autophagy initiation and lysosome-dependent degradation.
  • Analyzed the functional consequences of the NSP6 L37F polymorphism.

Main Results:

  • SARS-CoV-2 NSP6 activates Beclin1 to promote autophagy initiation.
  • NSP6 inhibits later stages of autophagy by blocking lysosome-dependent degradation through Mucolipin 1 (MLN1) inhibition.
  • The NSP6 L37F variant enhances autophagy initiation but shows reduced inhibition of lysosomal degradation.

Conclusions:

  • SARS-CoV-2 NSP6 exhibits a dual regulatory role in autophagy, promoting initiation and inhibiting degradation.
  • This dual mechanism may contribute to viral pathogenesis by manipulating host cell autophagy.
  • Findings offer potential targets for therapeutic interventions against SARS-CoV-2.
Keywords:
Beclin1COVID-19MLN1NSP6SARS-CoV-2autophagy–lysosome degradation

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