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ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication

Yafei Qu1, Xin Wang1, Yunkai Zhu2

  • 1Research Center of Translational Medicine, Shanghai Institute of Immunology, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Frontiers in Cell and Developmental Biology
|August 13, 2021
PubMed

Insights

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection causes incomplete autophagy. The viral protein ORF3a disrupts host cell machinery, inhibiting autophagosome maturation and aiding viral replication, suggesting autophagy as a therapeutic target for COVID-19.

Area of Science:

  • Virology
  • Cell Biology
  • Immunology

Background:

  • Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) drives the COVID-19 pandemic, necessitating understanding of cellular responses.
  • Autophagy, crucial for cellular homeostasis, involves Beclin 1-based complexes regulating autophagosome formation and maturation.

Purpose of the Study:

  • To investigate the impact of SARS-CoV-2 infection on host cell autophagy.
  • To identify specific viral proteins involved in modulating the autophagy pathway.
  • To elucidate the mechanism by which SARS-CoV-2 interferes with autophagy for replication.

Main Methods:

  • Analysis of autophagy response in SARS-CoV-2 infected cells.
  • Genetic knockout of essential autophagy genes to assess viral replication.
  • Screening of 26 SARS-CoV-2 viral proteins for autophagy modulation.
  • Co-immunoprecipitation assays to determine protein interactions between viral proteins and autophagy regulators.

Main Results:

  • SARS-CoV-2 infection leads to incomplete autophagy, characterized by increased autophagosome formation but impaired maturation.
  • Knocking out key autophagy genes significantly reduces SARS-CoV-2 replication.
  • The SARS-CoV-2 ORF3a protein alone is sufficient to induce incomplete autophagy.
  • ORF3a interacts with UVRAG, inhibiting the Beclin-1-Vps34-UVRAG complex (PI3KC3-C2) while facilitating the Beclin-1-Vps34-Atg14 complex (PI3KC3-C1).
  • SARS-CoV ORF3a, despite high sequence identity, does not affect cellular autophagy.

Conclusions:

  • SARS-CoV-2 ORF3a hijacks host autophagy machinery by selectively inhibiting autophagosome maturation, thereby promoting viral replication.
  • Targeting the host autophagic pathway presents a potential therapeutic strategy for treating COVID-19.
Keywords:
COVID-19ORF3aSARS-CoV-2UVRAGautophagy

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