title: Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors.
abstract: 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.
authors.affiliation: Department of Medicine, Laboratory of Immunopathology, Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Xiong
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Justin
authors.initials: J
authors.lastname: Nguyen
authors.forename: Bernard
authors.initials: B
authors.lastname: Ng
authors.forename: Huifang
authors.initials: H
authors.lastname: Lu
authors.forename: John
authors.initials: J
authors.lastname: Brendese
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
mesh_terms: 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*
chemical_list: C494811:BCL2L1 protein, human; C501689:E protein, SARS coronavirus; D006133:Growth Substances; D014759:Viral Envelope Proteins; D000086082:Viroporin Proteins; D051020:bcl-X Protein