Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option

Nat Genet. 2020 Dec;52(12):1294-1302. doi: 10.1038/s41588-020-00732-8. Epub 2020 Oct 19.

Abstract

Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a regulator of several physiological processes. ACE2 has recently been proposed to be interferon (IFN) inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of IFN treatment in coronavirus disease 2019. Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a new isoform of ACE2, generated by co-option of intronic retroelements as promoter and alternative exon. The new transcript, termed MIRb-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and is highly responsive to IFN stimulation. In contrast, canonical ACE2 expression is unresponsive to IFN stimulation. Moreover, the MIRb-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and is therefore unlikely to contribute to or enhance viral infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / biosynthesis*
  • Angiotensin-Converting Enzyme 2 / genetics
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Enzyme Induction
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Viral
  • HEK293 Cells
  • Humans
  • Interferons / metabolism*
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Protein Stability
  • RNA-Seq
  • Receptors, Coronavirus / metabolism
  • Retroelements / genetics*
  • SARS-CoV-2 / metabolism
  • Tissue Distribution
  • Vero Cells

Substances

  • Isoenzymes
  • Receptors, Coronavirus
  • Retroelements
  • Interferons
  • Angiotensin-Converting Enzyme 2