RRC ID 43365
著者 Haga S, Yamamoto N, Nakai-Murakami C, Osawa Y, Tokunaga K, Sata T, Yamamoto N, Sasazuki T, Ishizaka Y.
タイトル Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry.
ジャーナル Proc Natl Acad Sci U S A
Abstract 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-alpha-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-alpha 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.
巻・号 105(22)
ページ 7809-14
公開日 2008-6-3
DOI 10.1073/pnas.0711241105
PII 0711241105
PMID 18490652
PMC PMC2409424
MeSH ADAM Proteins / metabolism* ADAM17 Protein Angiotensin-Converting Enzyme 2 Animals Cell Line Humans Membrane Glycoproteins / metabolism* Mice Peptidyl-Dipeptidase A / genetics Peptidyl-Dipeptidase A / metabolism* Protein Structure, Tertiary / genetics RNA, Messenger / metabolism RNA, Small Interfering / genetics Sequence Deletion Severe acute respiratory syndrome-related coronavirus / genetics Severe acute respiratory syndrome-related coronavirus / physiology* Spike Glycoprotein, Coronavirus Tumor Necrosis Factor-alpha / metabolism* Viral Envelope Proteins / metabolism* Virus Internalization*
IF 9.412
引用数 95
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 293T(RCB2202)