nference

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

Abstract: Molecular mimicry of host proteins is an evolutionary strategy adopted by viruses to evade immune surveillance and exploit host cell systems. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site (RRARSVAS), absent in any previous coronavirus sequenced, that results in mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic truncation at this ENaC-α cleavage site causes aldosterone dysregulation in patients, highlighting the functional importance of the mimicked SARS-CoV-2 peptide. Single cell RNA-seq from 65 studies shows significant overlap between the expression of ENaC-α and ACE2, the putative receptor for the virus, in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular fingerprint with amino acid cleavage signatures of 178 human proteases shows the potential for tissue-specific proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. We extrapolate that the evolution of SARS-CoV-2 into a global coronavirus pandemic may be in part due to its targeted mimicry of human ENaC and hijack of the associated host proteolytic network.
  • Authors:
  • Praveen Anand1,
  • Arjun Puranik2,
  • Murali Aravamudan2,
  • AJ Venkatakrishnan2,
  • Venky Soundararajan2
  • 1nference Labs, Murugesh Pallya, Bengaluru, Karnataka 560047, India
  • 2nference, Inc, One Main Street, East Arcade, Cambridge, MA 02142, USA
  • Correspondence:
  • Affiliation:
  • Timeline:
  • Received: May 5, 2020
  • Accepted: May 25, 2020
  • Published: May 26, 2020 (v1)
  • Copyright:
  • © 2020, Anand et al.
  • This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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  • Affiliation:
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  • Timeline:
  • Received: May 5, 2020
  • Accepted: May 25, 2020
  • Published: May 26, 2020 (v1)
  • Copyright:
  • © 2020, Anand et al.
  • This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
  • Related Tweets:
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