Selective involvement of BH3-only proteins and differential targets of Noxa in diverse apoptotic pathways

L. Zhang, H. Lopez, N. M. George, X. Liu, X. Pang, X. Luo

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

The BH3-only proteins of the Bcl-2 family are known to mediate mitochondrial dysfunction during apoptosis. However, the identity of the critical BH3-only proteins and the mechanism of their action following treatment by diverse apoptotic stimuli remain to be fully resolved. We therefore used RNAi to screen the entire Bcl-2 family for their involvement in three major apoptotic pathways in HeLa cells. We found that Bcl-xL and Mcl-1 are major inhibitors of apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL), endoplasmic reticulum (ER) stress, and proteasome inhibition. Among the 10 BH3-only proteins, Bid and Noxa were found to be critically involved in TRAIL-induced apoptosis, in which Noxa participates by constitutively binding to Mcl-1. Bim and Noxa were found to be necessary for ER stress-induced apoptosis, in which Noxa assisted Bim function by sequestering Mcl-1 and binding to Bcl-xL. As a critical BH3-only protein, Noxa was strongly upregulated and became associated with both Mcl-1 and Bcl-xL during apoptosis induced by proteasome inhibition. In addition, we found that Noxa became Mcl-1 free following treatment by ER stress and proteasome inhibition, but not after TRAIL treatment. These results defined the critical Bcl-2 network during apoptosis and suggested that Noxa participated in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms.

Original languageEnglish (US)
Pages (from-to)864-873
Number of pages10
JournalCell Death and Differentiation
Volume18
Issue number5
DOIs
StatePublished - May 1 2011

Keywords

  • BH3-only
  • Bcl-2
  • apoptosis
  • mitochondria

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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