Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry.
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.
Haga
Shiori
S
Department of Intractable Diseases, International Medical Center of Japan, 162-8655 Tokyo, Japan.
Yamamoto
Norio
N
Nakai-Murakami
Chikako
C
Osawa
Yoshiaki
Y
Tokunaga
Kenzo
K
Sata
Tetsutaro
T
Yamamoto
Naoki
N
Sasazuki
Takehiko
T
Ishizaka
Yukihito
Y
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002460:Cell Line; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D064370:Spike Glycoprotein, Coronavirus; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053586:Virus Internalization
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064370:Spike Glycoprotein, Coronavirus; D014409:Tumor Necrosis Factor-alpha; D014759:Viral Envelope Proteins; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse