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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 \u03b1-subunit (ENaC-\u03b1). Genetic alteration of ENaC-\u03b1 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-\u03b1 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-\u03b1, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.<\/jats:p>","DOI":"10.7554\/elife.58603","type":"journal-article","created":{"date-parts":[[2020,5,26]],"date-time":"2020-05-26T08:00:47Z","timestamp":1590480047000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.58603","source":"Crossref","is-referenced-by-count":125,"title":["SARS-CoV-2 strategically mimics proteolytic activation of human ENaC"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2478-7042","authenticated-orcid":true,"given":"Praveen","family":"Anand","sequence":"first","affiliation":[{"name":"nference Labs, Bengaluru, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Puranik","sequence":"additional","affiliation":[{"name":"nference, Inc, Cambridge, United 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