2. Academic Validation
  3. Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

Interferons and viruses induce a novel truncated ACE2 isoform and not the full-length SARS-CoV-2 receptor

  • Nat Genet. 2020 Dec;52(12):1283-1293. doi: 10.1038/s41588-020-00731-9.
Olusegun O Onabajo # 1,  A Rouf Banday # 1,  Megan L Stanifer 2,  Wusheng Yan 1,  Adeola Obajemu 1,  Deanna M Santer 3,  Oscar Florez-Vargas 1,  Helen Piontkivska 4,  Joselin M Vargas 1,  Timothy J Ring 1,  Carmon Kee 5 6,  Patricio Doldan 5 6,  D Lorne Tyrrell 3,  Juan L Mendoza 7,  Steeve Boulant 5 6,  Ludmila Prokunina-Olsson 8
Affiliations

Affiliations

  • 1 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.
  • 3 Li Ka Shing Institute of Virology and Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada.
  • 4 Department of Biological Sciences and Brain Health Research Institute, Kent State University, Kent, OH, USA.
  • 5 Division of Cellular Polarity and Viral Infection, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 6 Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany.
  • 7 Pritzker School of Molecular Engineering and Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
  • 8 Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. prokuninal@mail.nih.gov.
  • # Contributed equally.
PMID: 33077916 DOI: 10.1038/s41588-020-00731-9
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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