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