Details

Autor(en) / Beteiligte

• Pazarentzos, Evangelos
• Mahul-Mellier, Anne-Laure
• Datler, Christoph
• Chaisaklert, Wanwisa
• Hwang, Ming-Shih
• Kroon, Jan
• Qize, Ding
• Osborne, Foy
• Al-Rubaish, Abdullah
• Al-Ali, Amein
• Mazarakis, Nicholas D
• Aboagye, Eric O
• Grimm, Stefan

Titel

I[kappa][Beta][alpha] inhibits apoptosis at the outer mitochondrial membrane independently of NF-[kappa]B retention

Ist Teil von

• The EMBO journal, 2014-12, Vol.33 (23), p.2814

Ort / Verlag

Heidelberg: Blackwell Publishing Ltd

Erscheinungsjahr

2014

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• I[kappa]B[alpha] resides in the cytosol where it retains the inducible transcription factor NF-[kappa]B. We show that I[kappa]B[alpha] also localises to the outer mitochondrial membrane (OMM) to inhibit apoptosis. This effect is especially pronounced in tumour cells with constitutively active NF-[kappa]B that accumulate high amounts of mitochondrial I[kappa]B[alpha] as a NF-[kappa]B target gene. 3T3 I[kappa]B[alpha]-/- cells also become protected from apoptosis when I[kappa]B[alpha] is specifically reconstituted at the OMM. Using various I[kappa]B[alpha] mutants, we demonstrate that apoptosis inhibition and NF-[kappa]B inhibition can be functionally and structurally separated. At mitochondria, I[kappa]B[alpha] 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[kappa]B[alpha] 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 I[kappa]B[alpha] in guarding the integrity of the OMM against apoptosis induction and open possibilities for more specific interference in tumours with deregulated NF-[kappa]B. Synopsis IkB[alpha] interacts with VDAC and hexokinase II at mitochondria to prevent cytochrome c release and apoptosis of tumor cells, independently of its function as an NF-[kappa]B inhibitor. I[kappa]B[alpha] resides at the outer mitochondrial membrane. I[kappa]B[alpha] associates with VDAC1 and hexokinase II to inhibit the dissociation of HKII. I[kappa]B[alpha] prevents Bax-mediated cytochrome c release for apoptosis induction. This novel anti-apoptotic activity of I[kappa]B[alpha] is independent of NF-[kappa]B retention.