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DYRK1A promotes viral entry of highly pathogenic human coronaviruses in a kinase-independent manner

Madison S Strine1,2, Wesley L Cai3, Jin Wei1,2,4

  • 1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Plos Biology
|June 13, 2023
PubMed

Insights

Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A (DYRK1A) is a novel host factor essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and other pathogenic human coronaviruses entry. DYRK1A regulates ACE2 and DPP4 expression, impacting COVID-19 susceptibility.

Area of Science:

  • Virology
  • Molecular Biology
  • Genetics

Background:

  • Identifying host genes is crucial for understanding viral pathogenesis and discovering new therapeutic targets for coronaviruses like SARS-CoV-2.
  • Previous genome-wide screens identified some host factors for human coronaviruses, but few were common across different viruses and cell types.

Purpose of the Study:

  • To identify novel host factors regulating entry of highly pathogenic human coronaviruses, including SARS-CoV-2.
  • To investigate the role of DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A) in coronavirus infection and its mechanism of action.

Main Methods:

  • Genome-wide CRISPR/Cas9 screening was employed to identify proviral host factors.
  • Functional assays were performed to assess the role of DYRK1A in regulating ACE2 and DPP4 transcription.
  • Studies utilized cell lines from human and nonhuman primate origins to validate findings across species.

Main Results:

  • DYRK1A was identified as a host factor required by diverse coronaviruses (SARS-CoV, SARS-CoV-2, MERS-CoV).
  • DYRK1A regulates ACE2 and DPP4 transcription independently of its kinase activity, promoting viral entry.
  • DYRK1A enhances DNA accessibility at the ACE2 promoter and a distal enhancer, boosting gene expression.

Conclusions:

  • DYRK1A is a novel proviral host factor that regulates ACE2 and DPP4 expression, influencing susceptibility to multiple pathogenic human coronaviruses.
  • DYRK1A's role in regulating viral entry is conserved across species, highlighting its potential as a therapeutic target for COVID-19 and related diseases.

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