The inducible transcription factor NF-κB is tightly regulated by the
inhibitory IκB-family of proteins that associate with the transcription factor and act
in response to stress stimuli. The best studied inhibitory protein is IκBα which
resides in the cytosol where it retains NF-κB. Our study shows that IκBα also
associates with the outer mitochondrial membrane (OMM) and exerts an
unexpected novel anti-apoptotic function, independent of NF-κB inhibition. IκBα-/-
cells become refractory to apoptosis when IκBα is specifically reconstituted at the
OMM. We found that cancer cells with constitutively active NF-κB accumulate IκBα
at the OMM and when its expression is down-regulated these cells are sensitised
to apoptosis. At the OMM IκBα associates with VDAC1 and hexokinase II (HKII).
Our findings show that IκBα inhibits the dissociation of HKII from VDAC1 and
prevents Bax-mediated cytochrome c release. Deletion mutants of IκBα reveal a
domain necessary for apoptosis inhibition that is different from the domain for
NF-κB retention, thereby separating the two functions. These results reveal an
unexpected activity of IκΒα in guarding the integrity of the OMM against
apoptosis induction and open possibilities for more specific interference in
diseases involving deregulated NF-κB.