Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling.
Severe acute respiratory syndrome (SARS) is an acute infectious disease with significant mortality. A typical clinical feature associated with SARS is pulmonary fibrosis and the associated lung failure. However, the underlying mechanism remains elusive. In this study, we demonstrate that SARS-associated coronavirus (SARS-CoV) nucleocapsid (N) protein potentiates transforming growth factor-beta (TGF-beta)-induced expression of plasminogen activator inhibitor-1 but attenuates Smad3/Smad4-mediated apoptosis of human peripheral lung epithelial HPL1 cells. The promoting effect of N protein on the transcriptional responses of TGF-beta is Smad3-specific. N protein associates with Smad3 and promotes Smad3-p300 complex formation while it interferes with the complex formation between Smad3 and Smad4. These findings provide evidence of a novel mechanism whereby N protein modulates TGF-beta signaling to block apoptosis of SARS-CoV-infected host cells and meanwhile promote tissue fibrosis. Our results reveal a novel mode of Smad3 action in a Smad4-independent manner and may lead to successful strategies for SARS treatment by targeting the TGF-beta signaling molecules.
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084.
Xingang
X
Zhao
Department of Pathology, University of Hong Kong, Hong Kong, China.
John M
JM
Nicholls
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084. Electronic address: ygchen@tsinghua.edu.cn.
Ye-Guang
YG
Chen
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D005355:Fibrosis / Q000473:pathology; D015967:Gene Expression Regulation, Viral; D006801:Humans; D051379:Mice; D019590:Nucleocapsid Proteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D019590:Nucleocapsid Proteins; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta