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

Ng, Kevin W.; Attig, Jan; Bolland, William; Young, George R.; Major, Jack; Wrobel, Antoni G.; Gamblin, Steve; Wack, Andreas; Kassiotis, George

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-inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of interferon treatment in Coronavirus disease 2019 (COVID-19). Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a novel isoform of ACE2, generated by co-option of intronic retroelements as promoter and alternative exon. The novel transcript, termed MIRb-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and is highly responsive to interferon stimulation. In stark contrast, canonical ACE2 expression is unresponsive to interferon 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.