tetano
Editor, Senior Moderator
Elife
. 2020 May 26;9:e58603.
doi: 10.7554/eLife.58603. Online ahead of print.
SARS-CoV-2 Strategically Mimics Proteolytic Activation of Human ENaC
Praveen Anand[SUP] 1 [/SUP], Arjun Puranik[SUP] 2 [/SUP], Murali Aravamudan[SUP] 3 [/SUP], A J Venkatakrishnan[SUP] 3 [/SUP], Venky Soundararajan[SUP] 3 [/SUP]
Affiliations
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.
Keywords: computational biology; human; human biology; medicine; mouse; systems biology; viruses.
. 2020 May 26;9:e58603.
doi: 10.7554/eLife.58603. Online ahead of print.
SARS-CoV-2 Strategically Mimics Proteolytic Activation of Human ENaC
Praveen Anand[SUP] 1 [/SUP], Arjun Puranik[SUP] 2 [/SUP], Murali Aravamudan[SUP] 3 [/SUP], A J Venkatakrishnan[SUP] 3 [/SUP], Venky Soundararajan[SUP] 3 [/SUP]
Affiliations
- PMID: 32452762
- DOI: 10.7554/eLife.58603
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.
Keywords: computational biology; human; human biology; medicine; mouse; systems biology; viruses.