Bcl-XL disrupts death-inducing signal complex formation in plasma membrane induced by hypoxia/reoxygenation

Xue Wang, Jinglan Zhang, Pyo Kim Hong, Yong Wang, Augustine M.K. Choi, Stefan W. Ryter

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Hypoxia/reoxygenation (H/R) causes cellular injury and death. The cell death pathways induced by H/R remain incompletely understood. H/R can induce Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of Bcl-XL, an anti-apoptotic Bcl-2-related protein, in H/R-induced cell death. The expression of Bcl-XL protected MLEC against H/R-induced cell death by blocking Bax and Bid translocation and inhibiting mitochondrial cytochrome c release. Bcl-XL expression inhibited caspase-8 cleavage and death-inducing signal complex (DISC) formation in plasma membrane. By isolating mitochondrial, nuclear, and Golgi fractions, we found that H/R induced DISC formation in these organelles. Bcl-XL expression inhibited DISC formation in the nuclear and Golgi fractions relative to LacZ-infected controls. In contrast, DISC formation was elevated in the mitochondrial fraction of Bcl-X L-infected cells. GRASP65, a Golgi-associated protein, physically associated with Fas and caspase-8; Bcl-XL expression decreased these associations. Bcl-XL expression also up-regulated FLIP, a caspase-8 inhibitor. In conclusion, Bcl-XL may inactivate caspase-8 by decreasing DISC formation in the plasma membrane, nucleus, and Golgi complex while diverting DISC formation to the mitochondria. The inhibitory effects of Bcl-XL on DISC formation may play significant roles in protecting endothelial cells from H/R-induced cell death.

Original languageEnglish (US)
Pages (from-to)1826-1833
Number of pages8
JournalFASEB Journal
Volume18
Issue number15
DOIs
StatePublished - Dec 2004

Keywords

  • Caspase-8
  • DISC
  • Hypoxia
  • Reoxygenation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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