Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor
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Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, utilizes angiotensin-converting enzyme 2 (ACE2) for entry into target cells. ACE2 has been proposed as an interferon-stimulated gene (ISG). Thus, interferon-induced variability in ACE2 expression levels could be important for susceptibility to COVID-19 or its outcomes. Here, we report the discovery of a novel, transcriptionally independent truncated isoform of ACE2, which we designate as deltaACE2 (dACE2). We demonstrate that dACE2, but not ACE2, is an ISG. In The Cancer Genome Atlas, the expression of dACE2 was enriched in squamous tumors of the respiratory, gastrointestinal and urogenital tracts. In vitro, dACE2, which lacks 356 amino-terminal amino acids, was non-functional in binding the SARS-CoV-2 spike protein and as a carboxypeptidase. Our results suggest that the ISG-type induction of dACE2 in IFN-high conditions created by treatments, an inflammatory tumor microenvironment or viral co-infections is unlikely to increase the cellular entry of SARS-CoV-2 and promote infection.
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A truncated form of ACE2 called deltaACE2, but not ACE2 itself, is an interferon-stimulated gene.
“In contrast to earlier reports suggesting ACE2 to be an interferon-stimulated gene (ISG), more recent evidence showed that a truncated form of ACE2 designated deltaACE2, but not ACE2 itself, is an ISG (Onabajo et al., 2020).”
From COVID-19 and the human innate immune system (2021) · cites this paper as Onabajo et al., 2020
DeltaACE2 neither binds the SARS-CoV-2 spike protein nor serves as a carboxypeptidase.
“DeltaACE2 neither binds the SARS-CoV-2 spike protein nor serves as a carboxypeptidase.”
From COVID-19 and the human innate immune system (2021) · cites this paper as Onabajo et al., 2020
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- Authors
- Onabajo, O. O., Banday, A. R., Stanifer, M. L., Yan, W., Obajemu, A., Santer, D. M., Florez-Vargas, O., Piontkivska, H., Vargas, J. M., Ring, T. J., Kee, C., Doldan, P., Tyrrell, D. L., Mendoza, J. L., Boulant, S., & Prokunina-Olsson, L.
- Affiliations
- National Institutes of Health (US)
- University Hospital Heidelberg (DE)
- University of Alberta (CA)
- Kent State University (US)
- German Cancer Research Center (DE)
- University of Chicago (US)
- ORCID
- Venue
- Nature Genetics
- Published
- 2020-10-19
- Volume
- 52
- Issue
- 12
- Pages
- 1283-1293
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC9377523
- OpenAlex
- W3093094957
- Cited by
- 261
- References
- 47
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 23 · 2023: 31 · 2022: 63 · 2021: 101 · 2020: 23
- FWCI
- 7.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, public-domain)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, public-domain)
- Funders
- Deutsche Forschungsgemeinschaft (416072091, 240245660, 272983813)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R21AG064479-01)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- ACE2, SARS-CoV-2, COVID-19 pandemic, interferon-stimulated genes, viral receptor, spike protein binding, carboxypeptidase activity, tumor expression, viral coinfection, interferon induction
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