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SARS-CoV-2 strategically mimics proteolytic activation of human ENaC.
Elife. 2020 05 26; 9E

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 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.

Authors+Show Affiliations

nference Labs, Bengaluru, India.nference, Inc, Cambridge, United States.nference, Inc, Cambridge, United States.nference, Inc, Cambridge, United States.nference, Inc, Cambridge, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32452762

Citation

Anand, Praveen, et al. "SARS-CoV-2 Strategically Mimics Proteolytic Activation of Human ENaC." ELife, vol. 9, 2020.
Anand P, Puranik A, Aravamudan M, et al. SARS-CoV-2 strategically mimics proteolytic activation of human ENaC. Elife. 2020;9.
Anand, P., Puranik, A., Aravamudan, M., Venkatakrishnan, A. J., & Soundararajan, V. (2020). SARS-CoV-2 strategically mimics proteolytic activation of human ENaC. ELife, 9. https://doi.org/10.7554/eLife.58603
Anand P, et al. SARS-CoV-2 Strategically Mimics Proteolytic Activation of Human ENaC. Elife. 2020 05 26;9 PubMed PMID: 32452762.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 strategically mimics proteolytic activation of human ENaC. AU - Anand,Praveen, AU - Puranik,Arjun, AU - Aravamudan,Murali, AU - Venkatakrishnan,A J, AU - Soundararajan,Venky, Y1 - 2020/05/26/ PY - 2020/05/05/received PY - 2020/05/25/accepted PY - 2020/5/27/pubmed PY - 2020/7/16/medline PY - 2020/5/27/entrez KW - COVID-19 KW - ENaC KW - SARS-CoV-2 KW - acute respiratory distress syndrome KW - computational biology KW - coronavirus KW - human KW - human biology KW - medicine KW - molecular mimicry KW - mouse KW - systems biology KW - virus JF - eLife JO - Elife VL - 9 N2 - 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. SN - 2050-084X UR - https://www.unboundmedicine.com/medline/citation/32452762/SARS_CoV_2_strategically_mimics_proteolytic_activation_of_human_ENaC_ L2 - https://doi.org/10.7554/eLife.58603 DB - PRIME DP - Unbound Medicine ER -