IκΒα inhibits apoptosis at the outer mitochondrial membrane independently of NF-κB retention

EMBO J. 2014 Dec 1;33(23):2814-28. doi: 10.15252/embj.201488183. Epub 2014 Oct 31.

Abstract

IκBα resides in the cytosol where it retains the inducible transcription factor NF-κB. We show that IκBα also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF-κB that accumulate high amounts of mitochondrial IκBα as a NF-κB target gene. 3T3 IκBα(-/-) cells also become protected from apoptosis when IκBα is specifically reconstituted at the OMM. Using various IκBα mutants, we demonstrate that apoptosis inhibition and NF-κB inhibition can be functionally and structurally separated. At mitochondria, IκBα stabilises the complex of VDAC1 and hexokinase II (HKII), thereby preventing Bax recruitment to VDAC1 and the release of cytochrome c for apoptosis induction. When IκBα is reduced in tumour cells with constitutively active NF-κB, they show an enhanced response to anticancer treatment in an in vivo xenograft tumour model. Our results reveal the unexpected activity of IκBα in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF-κB.

Keywords: IκΒα; VDAC1; apoptosis; cell death; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Line
  • Cytochromes c / metabolism
  • Female
  • Flow Cytometry
  • Hexokinase / metabolism
  • Humans
  • I-kappa B Proteins / metabolism*
  • Immunoprecipitation
  • Mice
  • Mice, Inbred BALB C
  • Microscopy, Fluorescence
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Membranes / physiology*
  • Models, Biological*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Oligonucleotides / genetics
  • Voltage-Dependent Anion Channel 1 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Oligonucleotides
  • VDAC1 protein, human
  • NF-KappaB Inhibitor alpha
  • Cytochromes c
  • Voltage-Dependent Anion Channel 1
  • Hexokinase