Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors.
One of the hallmark findings in patients suffering from SARS (severe acute respiratory syndrome) is lymphopenia, which is the result of massive lymphocyte death. SARS-CoV (SARS coronavirus), a novel coronavirus that has been etiologically associated with SARS cases, is homologous with MHV (murine hepatitis coronavirus), and MHV small envelope E protein is capable of inducing apoptosis. We hypothesized that SARS-CoV encodes a small envelope E protein that is homologous with MHV E protein, thus inducing T-cell apoptosis. To test this hypothesis, a cDNA encoding SARS-CoV E protein was created using whole gene synthesis. Our results showed that SARS-CoV E protein induced apoptosis in the transfected Jurkat T-cells, which was amplified to higher apoptosis rates in the absence of growth factors. However, apoptosis was inhibited by overexpressed antiapoptotic protein Bcl-xL. Moreover, we found that SARS-CoV E protein interacted with Bcl-xL in vitro and endogenous Bcl-xL in vivo and that Bcl-xL interaction with SARS-CoV E protein was mediated by BH3 (Bcl-2 homology domain 3) of Bcl-xL. Finally, we identified a novel BH3-like region located in the C-terminal cytosolic domain of SARS-CoV E protein, which mediates its binding to Bcl-xL. These results demonstrate, for the first time, a novel molecular mechanism of T-cell apoptosis that contributes to the SARS-CoV-induced lymphopenia observed in most SARS patients.
Yang
Yu
Y
Department of Medicine, Laboratory of Immunopathology, Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
Xiong
Zeyu
Z
Zhang
Sheng
S
Yan
Yan
Y
Nguyen
Justin
J
Ng
Bernard
B
Lu
Huifang
H
Brendese
John
J
Yang
Fan
F
Wang
Hong
H
Yang
Xiao-Feng
XF
D000595:Amino Acid Sequence; D017209:Apoptosis; D015967:Gene Expression Regulation, Viral; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism* / Q000821:virology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D000086082:Viroporin Proteins; D051020:bcl-X Protein / Q000378:metabolism*
C494811:BCL2L1 protein, human; C501689:E protein, SARS coronavirus; D006133:Growth Substances; D014759:Viral Envelope Proteins; D000086082:Viroporin Proteins; D051020:bcl-X Protein