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Human Betacoronavirus OC43 Interferes with the Integrated Stress Response Pathway in Infected Cells

Stacia M Dolliver1, Caleb Galbraith1, Denys A Khaperskyy1

  • 1Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada.

Viruses
|February 24, 2024
PubMed

Insights

Human coronavirus OC43 inhibits cellular stress responses to boost viral protein production. This study reveals OC43 disrupts the GADD34 feedback loop, independent of integrated stress response activation, ensuring viral replication.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Viruses employ strategies to optimize protein synthesis during infection.
  • The integrated stress response (ISR) halts cellular translation via eIF2α phosphorylation.
  • Human coronavirus OC43 (HCoV-OC43) was previously shown to inhibit eIF2α phosphorylation.

Purpose of the Study:

  • To investigate HCoV-OC43's modulation of the ISR.
  • To determine the role of GADD34 in HCoV-OC43-mediated ISR inhibition.

Main Methods:

  • Infection of cells with HCoV-OC43.
  • Analysis of eIF2α phosphorylation levels.
  • Measurement of GADD34 expression and induction.
  • Assessment of ISR activation using stress inducers.

Main Results:

  • HCoV-OC43 strongly induced GADD34 expression in infected cells.
  • GADD34 upregulation by HCoV-OC43 was independent of ISR activation.
  • GADD34 was not essential for HCoV-OC43's inhibition of eIF2α phosphorylation.
  • HCoV-OC43 actively inhibits eIF2α phosphorylation.

Conclusions:

  • HCoV-OC43 disrupts the GADD34 negative feedback loop controlling eIF2α phosphorylation.
  • This disruption is uncoupled from ISR activation, facilitating viral protein synthesis.
  • A complex interplay exists between HCoV-OC43 and the host ISR, favoring viral replication.
Keywords:
ATF4GADD34PERKPKRbetacoronavirus OC43integrated stress response

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