title: IκΒα inhibits apoptosis at the outer mitochondrial membrane independently of NF-κB retention.
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.
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK evangelos.pazarentzos@ucsf.edu.
authors.forename: Evangelos
authors.identifier: http://orcid.org/0000-0002-5453-1646
authors.initials: E
authors.lastname: Pazarentzos
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mahul-Mellier
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Christoph
authors.initials: C
authors.lastname: Datler
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Wanwisa
authors.initials: W
authors.lastname: Chaisaklert
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Ming-Shih
authors.initials: MS
authors.lastname: Hwang
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Kroon
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Ding
authors.initials: D
authors.lastname: Qize
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Foy
authors.initials: F
authors.lastname: Osborne
authors.affiliation: Prince Mohammed Center for Research & Consultation Studies, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al-Rubaish
authors.affiliation: Prince Mohammed Center for Research & Consultation Studies, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Amein
authors.initials: A
authors.lastname: Al-Ali
authors.affiliation: Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mazarakis
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, UK.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
authors.affiliation: Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Grimm
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009841:Oligonucleotides; C494762:VDAC1 protein, human; D000072000:NF-KappaB Inhibitor alpha; D045304:Cytochromes c; D050995:Voltage-Dependent Anion Channel 1; D006593:Hexokinase
keywords: IκΒα; VDAC1; apoptosis; cell death; mitochondria