ACE2 and gut amino acid transport

Abstract

ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.

Human Taste Cells Express ACE2: a Portal for SARS-CoV-2 Infection

“…The presence of ACE2 on Type II cells specifically is very intriguing because these are the cells that 'taste' amino acids and ACE2 in the gut has been shown to dimerize with amino acid transporters where it plays a vital role in efficient amino acid absorption. 27 We hypothesize that ACE2 is also on the chemosensory cells present in airways as their cellular machinery is similar to Type II cells in taste buds. They contain bitter receptors activated by ligands such cycloheximide, a bitter receptor agonist, and require PLCβ 2 for signal transduction.…”

Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs

“…8a-b), as previously. Using these 2 assays, we observed that induction of both HNF1B and NFE2 improved viral entry, but not TP73 or SLC6A19, which was surprising for the latter as it is a known partner of ACE2 33 . In line with this, we observed that, despite differences in ACE2 levels in the 2 negative control cell lines, induction of HNF1B and NFE2 seemed to increase ACE2 expression, contrary to that of TP73 or SLC6A19 (Fig.…”

“…Assuringly, the top-scoring proviral (sensitization) hit was ACE2. Several solute carrier (SLC) transport channels also scored on this side of the screen, including SLC6A19 (rank 8), which is a known partner of ACE2 33 . Furthermore, SLC6A14 (rank 2) has been implicated in cystic fibrosis progression and shown to regulate the attachment of Pseudomonas to human bronchial epithelial cells 34 .…”

Pathophysiological mechanisms underlying gastrointestinal symptoms in patients with COVID-19

“…In the gut, ACE2 has a completely different function independent of RAS. ACE2 stabilizes neutral amino acid transporters, such as B0AT1 and loss of ACE2 compromises intestinal uptake of certain dietary amino acids, such as tryptophan[ 20 ]. Because tryptophan plays an important role in immunity, ACE2 knockout mice exhibited altered gut microbiota and developed more severe dextran sulfate sodium–induced colitis compared with wild-type control mice[ 21 ].…”