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

Elife. 2020 May 26;9:e58603. doi: 10.7554/eLife.58603.


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.

Keywords: COVID-19; ENaC; SARS-CoV-2; acute respiratory distress syndrome; computational biology; coronavirus; human; human biology; medicine; molecular mimicry; mouse; systems biology; virus.

Plain Language Summary

Viruses hijack the cellular machinery of humans to infect their cells and multiply. The virus causing the global COVID-19 pandemic, SARS-CoV-2, is no exception. Identifying which proteins in human cells the virus co-opts is crucial for developing new ways to diagnose, prevent and treat COVID-19 infections. SARS-CoV-2 is covered in spike-shaped proteins, which the virus uses to gain entry into cells. First, the spikes bind to a protein called ACE2, which is found on the cells that line the respiratory tract and lungs. SARS-CoV-2 then exploits enzymes called proteases to cut, or cleave, its spikes at a specific site which allows the virus to infiltrate the host cell. Proteases identify which proteins to target based on the sequence of amino acids – the building blocks of proteins – at the cleavage site. However, it remained unclear which human proteases SARS-CoV-2 co-opts and whether its cut site is similar to human proteins. Now, Anand et al. show that the spike proteins on SARS-CoV-2 may have the same sequence of amino acids at its cut site as a human epithelial channel protein called ENaC-α. This channel is important for maintaining the balance of salt and water in many organs including the lungs. Further analyses showed that ENaC-α is often found in the same types of human lung and respiratory tract cells as ACE2. This suggests that SARS-CoV-2 may use the same proteases that cut ENaC-α to get inside human respiratory cells. It is possible that by hijacking the cutting mechanism for ENaC-α, SARS-CoV-2 interferes with the balance of salt and water in the lungs of COVID-19 patients. This may help explain why the virus causes severe respiratory symptoms. However, more studies are needed to confirm that the proteases that cut ENaC-α also cut the spike proteins on SARS-CoV-2, and how this affects the respiratory health of COVID-19 patients.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Betacoronavirus / genetics
  • Betacoronavirus / metabolism*
  • Betacoronavirus / pathogenicity
  • COVID-19
  • Coronavirus Infections / virology*
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Host-Pathogen Interactions
  • Humans
  • Molecular Mimicry*
  • Pandemics
  • Peptide Hydrolases / metabolism*
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / virology*
  • Proteolysis
  • SARS-CoV-2
  • Substrate Specificity
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*


  • Epithelial Sodium Channels
  • S envelope protein, hepatitis B virus
  • SCNN1A protein, human
  • Viral Envelope Proteins
  • Viral Proteins
  • Peptide Hydrolases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2

Grant support

The authors declare that there was no external funding for this work.