Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors

Biochem J. 2005 Nov 15;392(Pt 1):135-43. doi: 10.1042/BJ20050698.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Apoptosis*
  • Gene Expression Regulation, Viral
  • Growth Substances / metabolism
  • Humans
  • Jurkat Cells
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • SARS Virus / physiology*
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / virology
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism*
  • bcl-X Protein / metabolism*

Substances

  • BCL2L1 protein, human
  • E protein, SARS coronavirus
  • Growth Substances
  • Viral Envelope Proteins
  • bcl-X Protein