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

ELife
Praveen AnandVenky Soundararajan

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.

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Citations

Sep 25, 2020·Emerging Microbes & Infections·Khalid MunirXin Zhao
Aug 14, 2020·Physiology·Mary Kathryn BohnKhosrow Adeli
Jul 2, 2020·Genes and Immunity·Daniel PeckhamAnil Mehta
Oct 29, 2020·International Reviews of Immunology·Ashutosh KumarKamla Kant
Oct 22, 2020·Journal of Medical Virology·Ashutosh KumarKamla Kant
Jan 21, 2021·Experimental Biology and Medicine·Suresh MishraBl Grégoire Nyomba
Dec 18, 2020·Current Opinion in Rheumatology·Yu LiuQianjin Lu
Feb 16, 2021·Frontiers in Cellular and Infection Microbiology·Elisavet StavropoulouEugenia Bezirtzoglou
Feb 25, 2021·Journal of the Royal Society, Interface·William CaseyBud Mishra
Feb 25, 2021·Journal of Ginseng Research·Won Sik Lee, Dong-Kwon Rhee
Mar 28, 2021·European Journal of Clinical Pharmacology·Suzy HuijghebaertGuido Vanham
Apr 10, 2021·Frontiers in Human Neuroscience·Hale Yapici-EserYasemin Gursoy-Ozdemir
May 6, 2021·Amino Acids·Pawan Kumar RaghavDinesh Kumar
Jul 24, 2021·Molecular Biology Reports·K A DvornikovaA Lerner
Jul 2, 2021·Biophysical Journal·Stephen N Grant, Henry A Lester
Aug 4, 2021·Journal of Medicinal Chemistry·Essam Eldin A OsmanNouri Neamati
Aug 16, 2021·Molecular Biology Reports·Maryam NooriSaeid Safiri

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Methods Mentioned

BETA
RNA-seq
scRNA-seq

Software Mentioned

JalView
Clustal

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