SARS-CoV-2 strategically mimics proteolytic activation of human ENaC
Abstract
Molecular mimicry is an evolutionary strategy adopted by viruses to exploit the host cellular machinery. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site, absent in any previous coronavirus sequenced, resulting in striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic alteration of ENaC-α causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 65 studies shows significant overlap between expression of ENaC-α and the viral receptor ACE2 in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular characterization with cleavage signatures of 178 proteases highlights proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. Evolution of SARS-CoV-2 into a global pandemic may be driven in part by its targeted mimicry of ENaC-α, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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The authors declare that there was no external funding for this work.
Reviewing Editor
- Gian Paolo Rossi, University of Padova, Italy
Version history
- Received: May 5, 2020
- Accepted: May 25, 2020
- Accepted Manuscript published: May 26, 2020 (version 1)
- Version of Record published: July 8, 2020 (version 2)
Copyright
© 2020, Anand et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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