Journal Article

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

Filler, Renata B., Hanna, Ruth E., Konermann, Silvana, Cervantes, Kasey S., Hulme, Christopher, Doench, John G., Wei, Jin, Schofield, Kevin, Sarnik, Sylvia, Yan, Qin, Cai, Wesley L., Biering, Scott B., Strine, Madison S., DeWeirdt, Peter C., Kadoch, Cigall, Wilen, Craig B., Alfajaro, Mia Madel, Chow, Ryan D., Patil, Ajinkya, Collings, Clayton K., Hsu, Patrick D.

2023

Overview

Identifying host genes essential for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has the potential to reveal novel drug targets and further our understanding of Coronavirus Disease 2019 (COVID-19). We previously performed a genome-wide CRISPR/Cas9 screen to identify proviral host factors for highly pathogenic human coronaviruses. Few host factors were required by diverse coronaviruses across multiple cell types, but DYRK1A was one such exception. Although its role in coronavirus infection was previously undescribed, DYRK1A encodes D ual Specificity T y rosine Phosphorylation R egulated K inase 1A and is known to regulate cell proliferation and neuronal development. Here, we demonstrate that DYRK1A regulates ACE2 and DPP4 transcription independent of its catalytic kinase function to support SARS-CoV, SARS-CoV-2, and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) entry. We show that DYRK1A promotes DNA accessibility at the ACE2 promoter and a putative distal enhancer, facilitating transcription and gene expression. Finally, we validate that the proviral activity of DYRK1A is conserved across species using cells of nonhuman primate and human origin. In summary, we report that DYRK1A is a novel regulator of ACE2 and DPP4 expression that may dictate susceptibility to multiple highly pathogenic human coronaviruses.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ACE2 / Angiotensin-Converting Enzyme 2 / Animals / Biology and life sciences / Cell cycle / Cell proliferation / Coronaviridae / Coronaviruses / COVID-19 / COVID-19 - genetics / COVID-19 - metabolism / CRISPR / Cyclin-dependent kinases / Deoxyribonucleic acid / Dipeptidyl Peptidase 4 / DNA / Down syndrome / Dyrk Kinases / Epidemics / Fatalities / Gene expression / Genes / Genetic aspects / Genomes / Glycoproteins / Health aspects / Humans / Infections / Kinases / Localization / Medicine and health sciences / Middle East respiratory syndrome / Middle East Respiratory Syndrome Coronavirus - genetics / Pathogenesis / Phosphorylation / Protein kinases / Proteins / Respiratory diseases / SARS-CoV-2 - genetics / Severe acute respiratory syndrome coronavirus 2 / Severe acute respiratory syndrome-related coronavirus - genetics / Therapeutic targets / Tyrosine / Viral diseases / Viral infections / Virus Internalization / Virus research