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Authors: Onabajo et al 

Journal/ Pre-Print:bioRxiv 

Tags: Bioinformatics, Cell Biology, Immunology/Immunity, Inflammation, Molecular biology, Virology 

Research Highlights

  1. ACE2 is expressed from three different promoters, two encoding full-length ACE2 and the third a truncated version, dACE2, missing the first 356 N-terminal amino acids. 

  1. dACE2, but not ACE2, is the interferon-responsive gene. 

  1. dACE2 does not bind SARS-CoV-2 spike protein and does not function as a carboxypeptidase. 

Summary

The authors found by total RNA-seq of a breast cancer cell line infected with Sendai virus, which strongly induces interferons (IFNs) and interferon-stimulated genes (ISGs), that only a truncated version of ACE2, called dACE2 and missing the first 356 N-terminal amino acids, was induced. dACE2 is produced from a promoter located inside the ACE2 gene, which contains DNA motifs for transcription factors involved in the IFN signalling pathway. The authors show that dACE2, and not ACE2, is an ISG following respiratory viral infections, including with SARS-CoV-2, and in different types of cancers. Importantly, dACE2 does not bind SARS-CoV-2 spike protein and does not function as a carboxypeptidase, indicating that its induction by IFNs will not promote SARS-CoV-2 infection.   

Impact for SARS-CoV2/COVID19 research efforts  

Understand the immune response to SARS-CoV2/COVID19  

Respiratory viruses, including SARS-CoV-2, and interferons induce the expression of a truncated ACE2 protein (dACE2), not the full-length ACE2.   

Study Type  

  • In silico study / bioinformatics study 

  • In vitro study 

Strengths and limitations of the paper 

Novelty: The authors found that it is not ACE2 which is an interferon-responsive gene but a 5’ truncated version of ACE2, dACE2. dACE2 is specific to primates and seems to be under purifying selection. dACE2 is produced from a promoter located inside the ACE2 gene that contains multiple motifs predicted to be bound by transcription factors involved in the interferon signalling pathway.  

Standing in the field:Previous studies have found that ACE2 was an interferon-responsive gene. However, this conclusion was reached based on 3’end single cell RNA-seq, which does not provide information on the full-length of the mRNA isoforms. This study shows by using standard RNA-seq that the previously found ACE2 induction by SARS-CoV-2 and IFNs is in fact the induction of a truncated isoform of ACE2 (dACE2).   

Appropriate statistics: Yes 

Viral model used:SARS-CoV-2 

Translatability:As interferons are not inducing the full-length ACE2, which could have promoted SARS-CoV-2 infection, but a truncated version, which is not recognize by SARS-CoV-2, interferons can be used as treatments.  

Main limitations: The function of dACE2 remains unknown. However, as the 5’ end of dACE2 is specific to primates and seems to be under purifying selection (not fully tested in the manuscript but the sequence is conserved), it seems likely it has an important function. The induction of dACE2 by SARS-CoV-2 is not as clean as with other respiratory viruses but the trend supports the authors’ conclusions.