Aminopeptidase N is a major receptor for the enteropathogenic coronavirus TGEV

Delmas, Bernard; Gelfi, Jacqueline; L'Haridon, R.; Vogel, Lotte K.; Sjöström, Hans; Norén, Ove; Laude, Hubert

doi:10.1038/357417a0

Cited by 565 publications

(526 citation statements)

References 14 publications

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“…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.…”

Section: Discussionmentioning

confidence: 95%

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

Bridgen

Duarte

Tobler

et al. 1993

Journal of General Virology

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The nucleotide sequence of 1.7 kbp cDNA, comprising the region nearest the 3' end of the genome of the porcine epidemic diarrhoea virus (PEDV), has been independently determined for two European isolates of PEDV. Almost identical results were obtained for the two isolates, which were derived from cases of PEDV infection in Belgium and Britain in 1977 and 1987, respectively. The sequences contained a 1323 nucleotide (nt) open reading frame (ORF), which showed moderate identity to the nucleocapsid (N) gene of other coronaviruses. The greatest similarity at both the nucleic acid and protein levels was to the human coronavirus 229E.The PEDV N gene was, however, notably larger than that of the human 229E and porcine transmissible gastroenteritis viruses. This reflects the presence of a putative insertion of approximately 135 nt located towards the middle of the N gene. A second 336 nt ORF, which might encode a leucine-rich protein similar to, but shorter than, the bovine coronavirus internal protein was found within the PEDV N gene. Several RNA motifs typical of coronaviruses were also observed. These results confirm the earlier provisional classification of PEDV as a coronavirus.

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Section: Discussionmentioning

confidence: 95%

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

Bridgen

Duarte

Tobler

et al. 1993

Journal of General Virology

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“…APN is widely distributed in many cell types, and its role in hydrolyzing unsubstituted N-terminal residues with neutral side chains varies in different locations. In the epithelium of the renal proximal tubule, APN cleaves its only known natural substrate, angiotensin (ang) III, to ang IV; in synaptic membranes, APN metabolizes enkephalins and endorphins; in the heart, it is an integral component of cardiac remodeling postmyocardial infarction (5)(6)(7)(8)(9)(10); and in the respiratory system, APN is the cell surface receptor for certain human coronaviruses and potentially for the severe acute respiratory syndrome (SARS) virus (11)(12)(13). Additionally, APN functions in signal transduction, cell cycle control, and differentiation (14,15).…”

mentioning

confidence: 99%

Impaired angiogenesis in aminopeptidase N-null mice

Rangel

Sun

Guzman-Rojas

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports of in vivo inactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APNnull mice. These findings establish that APN-null mice develop normally without physiological alterations and can undergo physiological angiogenesis but show a severely impaired angiogenic response under pathological conditions. Finally, in addition to vascular biology research, APN-null mice may be useful reagents in other medical fields such as malignant, cardiovascular, immunological, or infectious diseases.CD13 ͉ knockout mice ͉ retinopathy ͉ vasculogenesis T he aminopeptidases are a large family of proteolytic enzymes that affect protein maturation, degradation, and regulation (1, 2). Aminopeptidase N (APN) is a membrane-bound zincdependent metalloprotease originally identified as a surface marker in myeloid cells (3,4). APN is widely distributed in many cell types, and its role in hydrolyzing unsubstituted N-terminal residues with neutral side chains varies in different locations. In the epithelium of the renal proximal tubule, APN cleaves its only known natural substrate, angiotensin (ang) III, to ang IV; in synaptic membranes, APN metabolizes enkephalins and endorphins; in the heart, it is an integral component of cardiac remodeling postmyocardial infarction (5-10); and in the respiratory system, APN is the cell surface receptor for certain human coronaviruses and potentially for the severe acute respiratory syndrome (SARS) virus (11-13). Additionally, APN functions in signal transduction, cell cycle control, and differentiation (14, 15).We have developed an in vivo system by using ligand peptides displayed on the surface of phage to study organ-and tumorspecific vascular homing; this methodology enables the identification of vascular markers (16,17). We have isolated phage displaying an asparagine-glycine-arginine (NGR)-containing peptide in a tumor-homing selection and have shown that these phage bind selectively to angiogenic blood vessels. When coupled to a cytotoxic drug (18) or fused to a proapoptotic peptide (19) or to tumor necrosis factor (20), NGR-targeted compounds were more effective and less toxic than the respective controls. The cell surface receptor fo...

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“…The receptors for the murine coronavirus mouse hepatitis virus are murine carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) and related murine glycoproteins in the carcinoembryonic antigen family in the Ig superfamily (4). The receptors for human coronavirus 229E (HCoV-229E), transmissible gastroenteritis virus of swine, and feline coronavirus in genetic group 1 are aminopeptidase N (APN) glycoproteins (5)(6)(7)(8).…”

mentioning

confidence: 99%

CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus

Jeffers

Tusell

Gillim-Ross

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

583

570

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Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus called SARS-CoV (1-3). The virus causes atypical pneumonia with diffuse alveolar damage with an overall mortality of Ϸ10% that ranges from 0% in children and 50% in persons over 65 (2). Coronaviruses bind to their glycoprotein receptors by the Ϸ200-kDa spike glycoprotein, S, on the viral envelope. Identification of virus receptors can provide insight into mechanisms of virus entry, tissue tropism, pathogenesis, and host range.Several types of receptors were previously identified for coronavirus S glycoproteins. The receptors for the murine coronavirus mouse hepatitis virus are murine carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) and related murine glycoproteins in the carcinoembryonic antigen family in the Ig superfamily (4). The receptors for human coronavirus 229E (HCoV-229E), transmissible gastroenteritis virus of swine, and feline coronavirus in genetic group 1 are aminopeptidase N (APN) glycoproteins (5-8).Angiotensin-converting enzyme 2 (ACE2) was found to be an efficient receptor for the S glycoprotein of SARS-CoV (9, 10). Because the Vero line of rhesus monkey kidney cells is highly susceptible to infection with SARS-CoV, Li et al. (9) used a codon-optimized soluble SARS-CoV spike glycoprotein (amino acids 12-672) fused to the Fc domain of human IgG1 to immunoprecipitate a putative receptor glycoprotein from Vero cell membranes and identified the simian ACE2 protein by mass spectrometry. They showed that expression of recombinant human ACE2 greatly enhanced the susceptibility of human 293T cells to infection by SARS-CoV. Wang et al. (10) independently demonstrated that human ACE2 is a receptor for SARS-CoV by transducing HeLa cells with a retrovirus library of cDNAs from Vero E6 cells and by using flow cytometry to select transduced cells that bound to purified soluble SARS-CoV S glycoprotein (amino acids 14-502) with a 6-histidine tag. They found that the simian cDNA in these cells, which encoded triosephosphate isomerase, enhanced expression of human ACE2 by inserting into the HeLa cell genome immediately upstream of the ACE2 ORF. Murine NIH 3T3 cells expressing recombinant human ACE2, but not those expressing recombinant triosephosphate isomerase, were susceptible to infection by HIV pseudovirus expressing SARS-CoV S protein.In this report, we describe the discovery of an additional receptor for SARS-CoV, CD209L (also called L-SIGN, DC-SIGNR, and DC-SIGN2) (11). Our strategy for identifying a SARS-CoV receptor was to transduce a human lung cDNA library carried by a retroviral vector into Chinese hamster ovary (CHO) cells and use flow cytometry to select transduced CHO cells that bound soluble, codon-optimized, c-myc-tagged SARSCoV S 590 glycoprotein (amino acids 1-590) expressed in 293T cells. The SARS-CoV S 590 -binding cells were then challenged with infectious SARS-CoV, and infection was demonstrated by detection of subgenomic viral RNA synthesis and immunofluorescence with antiviral antibody. The finding that ...

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Aminopeptidase N is a major receptor for the enteropathogenic coronavirus TGEV

Cited by 565 publications

References 14 publications

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

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

Impaired angiogenesis in aminopeptidase N-null mice

CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus

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