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 the striking mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel ?-subunit (ENaC-?). Genetic alteration of ENaC-? 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-? 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-?, a protein critical for the homeostasis of airway surface liquid, whose misregulation is associated with respiratory conditions.

SUBMITTER: Anand P 

PROVIDER: S-EPMC7343387 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature