Modulation of TNF-α-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-α production and facilitates viral entry

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 22; pp. 7809 - 7814
• Main Authors: Haga, Shiori, Yamamoto, Norio, Nakai-Murakami, Chikako, Osawa, Yoshiaki, Tokunaga, Kenzo, Sata, Tetsutaro, Yamamoto, Naoki, Sasazuki, Takehiko, Ishizaka, Yukihito
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.06.2008; National Acad Sciences
• Subjects: ADAM Proteins - metabolism; ADAM17 Protein; Animals; Biological Sciences; Cell Line; common cold; Coronavirus; Cultured cells; Enzymes; gene expression; HEK293 cells; Humans; Infections; Membrane Glycoproteins - metabolism; messenger RNA; Mice; mutants; pathogens; peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Protein Structure, Tertiary - genetics; quantitative polymerase chain reaction; Receptors; reverse transcriptase polymerase chain reaction; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; SARS virus; SARS Virus - genetics; SARS Virus - physiology; Sequence Deletion; Severe acute respiratory syndrome coronavirus; Small interfering RNA; Spike Glycoprotein, Coronavirus; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; Viral Envelope Proteins - metabolism; Viral infections; Virus Internalization; Viruses
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.0711241105

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a high-risk infectious pathogen. In the proposed model of respiratory failure, SARS-CoV down-regulates its receptor, angiotensin-converting enzyme 2 (ACE2), but the mechanism involved is unknown. We found that the spike protein of SARS-CoV (SARS-S) induced TNF-α-converting enzyme (TACE)-dependent shedding of the ACE2 ectodomain. The modulation of TACE activity by SARS-S depended on the cytoplasmic domain of ACE2, because deletion mutants of ACE2 lacking the carboxyl-terminal region did not induce ACE2 shedding or TNF-α production. In contrast, the spike protein of HNL63-CoV (NL63-S), a CoV that uses ACE2 as a receptor and mainly induces the common cold, caused neither of these cellular responses. Intriguingly, viral infection, judged by real-time RT-PCR analysis of SARS-CoV mRNA expression, was significantly attenuated by deletion of the cytoplasmic tail of ACE2 or knock-down of TACE expression by siRNA. These data suggest that cellular signals triggered by the interaction of SARS-CoV with ACE2 are positively involved in viral entry but lead to tissue damage. These findings may lead to the development of anti-SARS-CoV agents.