Human aminopeptidase N is a receptor for human coronavirus 229E

Abstract

Human coronaviruses (HCV) in two serogroups represented by HCV-229E and HCV-OC43 are an important cause of upper respiratory tract infections. Here we report that human aminopeptidase N, a cell-surface metalloprotease on intestinal, lung and kidney epithelial cells, is a receptor for human coronavirus strain HCV-229E, but not for HCV-OC43. A monoclonal antibody, RBS, blocked HCV-229E virus infection of human lung fibroblasts, immunoprecipitated aminopeptidase N and inhibited its enzymatic activity. HCV-229E-resistant murine fibroblasts became susceptible after transfection with complementary DNA encoding human aminopeptidase N. By contrast, infection of human cells with HCV-OC43 was not inhibited by antibody RBS and expression of aminopeptidase N did not enhance HCV-OC43 replication in mouse cells. A mutant aminopeptidase lacking the catalytic site of the enzyme did not bind HCV-229E or RBS and did not render murine cells susceptible to HCV-229E infection, suggesting that the virus-binding site may lie at or near the active site of the human aminopeptidase molecule.

Sequence determination of the nucleocapsid protein gene of the porcine epidemic diarrhoea virus confirms that this virus is a coronavirus related to human coronavirus 229E and porcine transmissible gastroenteritis virus

“…The sequence similarity observed between PEDV, HCV 229E and TGEV, together with the recent observation that HCV 229E and TGEV have the same cellular receptor (Yeager et al, 1992;Delmas et al, 1992), suggests a common origin of these viruses. Our data also suggest that different European strains of PEDV are very similar in sequence.…”

Structure of aminopeptidase N from Escherichia coli suggests a compartmentalized, gated active site

“…The homologous human enzyme hPepN is anchored in the plasma membrane and serves as a receptor for coronavirus and helps in its internalization (14). Elevated levels of expression of this enzyme have been associated with several cancers (15).…”

Targeting of aminopeptidase n to bile canaliculi correlates with secretory activities of the developing canalicular domain

“…The anti-APN monoclonal antibody (9B2) we had did not inhibit enzymatic activity of APN, and accordingly, had no effect on BC development (data not shown). In another set of experiments, we employed 2,2Ј-dipyridyl and 1,10-phenanthroline to inhibit the enzymatic activity of APN, 51,52 and both drugs could effectively block BC formation in a dose-responsive manner (Fig. 8, representative examples of 10 similar experiments).…”

“…Note that the concentrations used in this study were carefully titrated and were much lower than previous reports (for example, 1.5 mmol/L 1,10-phenanthroline and 2.5 mmol/L 2,2Ј-dipyridyl were typically used in Yeager et al). 52 At the dosages used, cells were dividing normally in the presence of both pharmacological reagents, and resumed to differentiate after wash-out of the drug (Tsai, Wu and Lin, manuscript in preparation).…”