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Regulation of autophagy by SARS-CoV-2: The multifunctional contributions of ORF3a

Mohd Shariq1, Asrar A Malik2, Javaid A Sheikh3

  • 1Inflammation Biology and Cell Signalling Laboratory, ICMR-National Institute of Pathology, New Delhi, India.

Journal of Medical Virology
|July 24, 2023
PubMed

Insights

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) disrupts autophagy by blocking autophagosome-lysosome fusion. The viral protein ORF3a plays a key role in this process, offering potential therapeutic targets.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) manipulates host cell processes to facilitate replication.
  • Autophagy, a cellular degradation pathway, is dysregulated by SARS-CoV-2, leading to viral accumulation.

Purpose of the Study:

  • To elucidate the specific mechanisms by which SARS-CoV-2, particularly its ORF3a protein, regulates autophagic flux.
  • To identify potential therapeutic targets for inhibiting SARS-CoV-2 replication by understanding its interaction with host autophagy machinery.

Main Methods:

  • Investigated the role of SARS-CoV-2 ORF3a protein in modulating autophagosome-lysosome fusion.
  • Analyzed protein-protein interactions involving ORF3a, including its association with UV radiation resistance-associated gene (UVRAG) and lipid kinase complexes (PIK3C3-1/2).
  • Examined ORF3a's effects on vesicle transport and membrane fusion events crucial for viral egress.

Main Results:

  • SARS-CoV-2 ORF3a blocks autophagosome-lysosome fusion by sequestering VPS39 and inhibiting SNARE complex assembly.
  • ORF3a promotes BECN1-HMGB1 interaction, leading to ER stress and reticulophagy.
  • ORF3a facilitates viral transport to the plasma membrane and induces lysosome-plasma membrane fusion for viral egress.

Conclusions:

  • SARS-CoV-2 ORF3a extensively manipulates host autophagy and membrane trafficking pathways.
  • Understanding these ORF3a-mediated mechanisms provides a basis for developing novel therapeutics targeting host-pathogen interactions to combat SARS-CoV-2 infection.
Keywords:
COVID-19HOPSSNAREautophagosomeendosomelysosome

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