SARS-CoV-2 strategically mimics proteolytic activation of human ENaC

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 the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel alpha-subunit (ENaC-alpha). Genetic alteration of ENaC-alpha causes aldosterone dysregulation in patients, highlighting that the FURIN site is critical for activation of ENaC. Single cell RNA-seq from 66 studies shows significant overlap between expression of ENaC-alpha and the viral receptor ACE2 in cell types linked to the cardiovascular-renalpulmonary 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-alpha, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.