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

Abstract

<jats:p>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 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 66 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.</jats:p>

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“…The viral entry mechanisms elucidated for SARS-CoV infection appear to be shared by SARS-CoV-2 (9,10). Additionally, SARS-CoV-2 uniquely possesses a "furin-like" cleavage site and is subject to processing during viral packaging by the intracellular proprotein convertase furin (11)(12)(13)(14).…”

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“…Importantly, ENaC needs to be proteolytically activated to function in controlling fluid reabsorption in the airways [ 40 ]. It is now reported that furin cleaves ENaC between arginine and serine residues in the 4th and 5th position (RSAR/SASS) to become activated [ 41 ].…”

“…When compared to SARS-CoV strains, a unique sequence insertion at the S1/S2 site of the spike protein is found in SARS-CoV-2 [ 42 ]. SARS-CoV-2 is coated with spike glycoprotein (S) that requires proteolytic cleavage for activation [ 41 ]. After interaction of S with the ACE2 receptor, SARS-CoV-2 entry into host cells occurs in two steps.…”

“…As explained earlier, the ACE2 receptors are present in a variety of different locations ranging from alveolar to intestinal cells [ 23 ]. Remarkably, ENaC-alpha are present in apical membranes of similar cells as those of ACE2 [ 23 , 41 , 43 ] leading to the hypothesis that SARS-CoV-2 leverages the protease network that is responsible for the cleavage of ENaC, which could subsequently lead to excessive sodium and liquid buildup in the lungs explaining clinical findings of ARDS. Anand et al found that the viral receptor ACE2, ENaC-alpha, and furin were coexpressed in the colon (immature enterocytes) and pancreas (ductal cells) of human tissue and tongue (keratinocytes) of mouse cells [ 41 ].…”

“…Remarkably, ENaC-alpha are present in apical membranes of similar cells as those of ACE2 [ 23 , 41 , 43 ] leading to the hypothesis that SARS-CoV-2 leverages the protease network that is responsible for the cleavage of ENaC, which could subsequently lead to excessive sodium and liquid buildup in the lungs explaining clinical findings of ARDS. Anand et al found that the viral receptor ACE2, ENaC-alpha, and furin were coexpressed in the colon (immature enterocytes) and pancreas (ductal cells) of human tissue and tongue (keratinocytes) of mouse cells [ 41 ]. Moreover, PCSK5 and PCSK7 are expressed in the intestinal, pancreas, nasal cavity, tracheal epithelial cells, and podocytes of the kidney, similarly to that of the ACE2 receptor [ 41 ].…”