A novel isoform ofACE2is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in the airways for SARS-CoV-2. ACE2 binding to SARS-CoV-2 protein Spike triggers viral fusion with the cell membrane, resulting in viral RNA genome delivery into the host. Despite ACE2’s critical role in SARS-CoV-2 infection, an understanding of ACE2 expression, including in response to viral infection, remains unclear.Until now ACE2 was thought to encode five transcripts and one 805 amino acid protein. Here we identify a novel short isoform of ACE2. Short ACE2 is expressed in the airway epithelium, the main site of SARS-CoV-2 infection; it is substantially upregulated in response to interferon stimulation and RV infection, but not in response to SARS-CoV-2 infection, and it shows differential regulation in asthma patients. This short isoform lacks SARS-CoV-2 spike glycoprotein high-affinity binding sites and altogether, our data are consistent with a model where short ACE2 may influence host susceptibility to SARS-CoV-2 infection.

SARS-CoV-2 receptor Angiotensin I-Converting Enzyme type 2 (ACE2) is expressed in human pancreatic β-cells and in the human pancreas microvasculature

“…ITGA5, as previously observed (60)]. Of interest, nasal epithelium, reported to represent the main reservoir of SARS-CoV-2 (61), showed higher levels of short-ACE2 vs. long-ACE2 (24).…”

“…According to the informations obtained by R&D and Abcam, while MAB933 and Ab15348 are reported to recognize the C-terminus portion of ACE2 (18-740aa and 788-805aa, respectively), Ab108252 is specifically designed to react with a linear peptide located in the N-terminal ACE2 protein sequence (200-300aa). It has been recently reported that a 459 aa short-ACE2 isoform (357-805aa of ACE2 + 10aa at N-terminus) can be co-expressed alongside the full-length ACE2 protein (1-805aa) ( Figure 3A ) (24,25); the short-ACE2 misses part of the N-terminal region targeted by Ab108252 antibody. We observed ACE2 islet-related signal using both MAB933 ( Figure 3B ) and Ab15348 ( Figure 3C ), but the Ab108252 antibody did not show any positivity within the islet parenchyma ( Figure 3D ), raising the possibility that the most prevalent ACE2 isoform within pancreatic islets is the short one.…”

“…However, these results are in line with Kusmartseva et al 2020 (57). Of note, Ab108252 monoclonal antibody specifically targets an epitope located in the N-terminal domain of ACE2 protein (200-300aa) which is missing in the recently discovered truncated ACE2 isoform (short-ACE2, 357-805aa) (24,25), thus being capable to recognize only the long-ACE2 isoform. On the contrary, by using two different antibodies (MAB933 and Ab15348) - which can recognize the C-terminal domain shared between short- and long-ACE2 - we obtained clear and concordant results, with identification of ACE2 in pancreatic islet endocrine cells in addition to the microvasculature.…”

“…These different cell types are thus potentially prone to SARS-CoV-2 infection. We also identified a differential distribution of the two recently discovered ACE2 isoforms (24,25). Exposure of EndoC-βH1 human beta-cell line and human pancreatic islets to pro-inflammatory cytokines significantly increased ACE2 expression.…”

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

“…However, a Myc-DDK-tagged or green fluorescent protein (GFP)-tagged MIRb-ACE2 protein product was detected following overexpression in T24 cells in the same study 24 . Moreover, a separate study 25 reported detection of the putative MIRb-ACE2 protein in primary nasal epithelial cells by western blotting using the same polyclonal anti-ACE2 serum (ab15348), raising the possibility that the protein can indeed be translated.…”