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

Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), as well as 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 an intronic long terminal repeat (LTR) retroelement promoter. The novel transcript, termed LTR16A1-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and, importantly, is highly responsive to interferon stimulation. In stark contrast, expression of canonical ACE2 is completely unresponsive to interferon stimulation. Moreover, the LTR16A1-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and therefore unlikely to contribute to or enhance viral infection.