ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification.

Angiotensin-converting enzyme 2 (ACE2), a counter regulator of the renin-angiotensin system, provides protection against several chronic diseases. Besides chronic diseases, ACE2 is the host receptor for SARS-CoV or SARS-CoV-2 virus, mediating the first step of virus infection. ACE2 levels are regulated by transcriptional, post-transcriptional, and post-translational regulation or modification. ACE2 transcription is enhanced by transcription factors including Ikaros, HNFs, GATA6, STAT3 or SIRT1, whereas ACE2 transcription is reduced by the transcription factor Brg1-FoxM1 complex or ERRα. ACE2 levels are also regulated by histone modification or miRNA-induced destabilization. The protein kinase AMPK, CK1α, or MAP4K3 phosphorylates ACE2 protein and induces ACE2 protein levels by decreasing its ubiquitination. The ubiquitination of ACE2 is induced by the E3 ubiquitin ligase MDM2 or UBR4 and decreased by the deubiquitinase UCHL1 or USP50. ACE2 protein levels are also increased by the E3 ligase PIAS4-mediated SUMOylation or the methyltransferase PRMT5-mediated ACE2 methylation, whereas ACE2 protein levels are decreased by AP2-mediated lysosomal degradation. ACE2 is downregulated in several human chronic diseases like diabetes, hypertension, or lung injury. In contrast, SARS-CoV-2 upregulates ACE2 levels, enhancing host cell susceptibility to virus infection. Moreover, soluble ACE2 protein and exosomal ACE2 protein facilitate SARS-CoV-2 infection into host cells. In this review, we summarize the gene regulation and post-translational modification of ACE2 in chronic disease and COVID-19. Understanding the regulation and modification of ACE2 may help to develop prevention or treatment strategies for ACE2-mediated diseases.