Amino Acid Sensor GCN2 Promotes SARS-CoV-2 Receptor ACE2 Expression in Response to Amino Acid Deprivation

Angiotensin-converting enzyme 2 (ACE2) has been identified as a primary receptor for severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2). Here, we investigated the expression regulation of ACE2 in enterocytes under amino acid deprivation conditions. In this study, we confirmed that ACE2 protein was highly expressed in intestinal epithelial cells in mice and found that ACE2 expression was upregulated upon all or only an essential amino acid deprivation in human colonic epithelial CCD841 cells. Furthermore, we found that knockdown of general control nonderepressible 2 ( GCN2 ) reduced intestinal ACE2 mRNA and protein levels in vitro and in vivo . Consistently, we revealed two GCN2 inhibitors, GCN2iB and GCN2-IN-1, downregulated ACE2 protein expression in CCD841 cells in a dose-dependent manner. Moreover, we found that increased ACE2 expression in response to leucine deprivation was GCN2 dependent. Through RNA-seq analysis, we identified that two novel transcription factors, MAFB and MAFF, positively regulated ACE2 expression under leucine deprivation in CCD841 cells. These findings demonstrate that amino acid deficiency increases ACE2 expression and thereby likely aggravates intestinal SARS-CoV-2 infection.