I??? inhibits apoptosis at the outer mitochondrial membrane independently of NF-?B retention.

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

SUBMITTER: Pazarentzos E 

PROVIDER: S-EPMC4282558 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature