000126654 001__ 126654
000126654 005__ 20240228140839.0
000126654 0247_ $$2doi$$a10.1074/jbc.M115.643064
000126654 0247_ $$2pmid$$apmid:26134559
000126654 0247_ $$2pmc$$apmc:PMC4571954
000126654 0247_ $$2ISSN$$a0021-9258
000126654 0247_ $$2ISSN$$a1083-351X
000126654 037__ $$aDKFZ-2017-02682
000126654 041__ $$aeng
000126654 082__ $$a570
000126654 1001_ $$0P:(DE-He78)a8657988a6082d4d90605e15cd5d3302$$aHamacher-Brady, Anne$$b0$$eFirst author$$udkfz
000126654 245__ $$aBax/Bak-dependent, Drp1-independent Targeting of X-linked Inhibitor of Apoptosis Protein (XIAP) into Inner Mitochondrial Compartments Counteracts Smac/DIABLO-dependent Effector Caspase Activation.
000126654 260__ $$aBethesda, Md.$$bSoc.$$c2015
000126654 3367_ $$2DRIVER$$aarticle
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000126654 3367_ $$2BibTeX$$aARTICLE
000126654 3367_ $$2ORCID$$aJOURNAL_ARTICLE
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000126654 520__ $$aEfficient apoptosis requires Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), which releases death-promoting proteins cytochrome c and Smac to the cytosol, which activate apoptosis and inhibit X-linked inhibitor of apoptosis protein (XIAP) suppression of executioner caspases, respectively. We recently identified that in response to Bcl-2 homology domain 3 (BH3)-only proteins and mitochondrial depolarization, XIAP can permeabilize and enter mitochondria. Consequently, XIAP E3 ligase activity recruits endolysosomes into mitochondria, resulting in Smac degradation. Here, we explored mitochondrial XIAP action within the intrinsic apoptosis signaling pathway. Mechanistically, we demonstrate that mitochondrial XIAP entry requires Bax or Bak and is antagonized by pro-survival Bcl-2 proteins. Moreover, intramitochondrial Smac degradation by XIAP occurs independently of Drp1-regulated cytochrome c release. Importantly, mitochondrial XIAP actions are activated cell-intrinsically by typical apoptosis inducers TNF and staurosporine, and XIAP overexpression reduces the lag time between the administration of an apoptotic stimuli and the onset of mitochondrial permeabilization. To elucidate the role of mitochondrial XIAP action during apoptosis, we integrated our findings within a mathematical model of intrinsic apoptosis signaling. Simulations suggest that moderate increases of XIAP, combined with mitochondrial XIAP preconditioning, would reduce MOMP signaling. To test this scenario, we pre-activated XIAP at mitochondria via mitochondrial depolarization or by artificially targeting XIAP to the intermembrane space. Both approaches resulted in suppression of TNF-mediated caspase activation. Taken together, we propose that XIAP enters mitochondria through a novel mode of mitochondrial permeabilization and through Smac degradation can compete with canonical MOMP to act as an anti-apoptotic tuning mechanism, reducing the mitochondrial contribution to the cellular apoptosis capacity.
000126654 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000126654 650_7 $$2NLM Chemicals$$aDIABLO protein, human
000126654 650_7 $$2NLM Chemicals$$aIntracellular Signaling Peptides and Proteins
000126654 650_7 $$2NLM Chemicals$$aMicrotubule-Associated Proteins
000126654 650_7 $$2NLM Chemicals$$aMitochondrial Proteins
000126654 650_7 $$2NLM Chemicals$$aX-Linked Inhibitor of Apoptosis Protein
000126654 650_7 $$2NLM Chemicals$$abcl-2 Homologous Antagonist-Killer Protein
000126654 650_7 $$2NLM Chemicals$$abcl-2-Associated X Protein
000126654 650_7 $$0555-60-2$$2NLM Chemicals$$aCarbonyl Cyanide m-Chlorophenyl Hydrazone
000126654 650_7 $$09007-43-6$$2NLM Chemicals$$aCytochromes c
000126654 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aCaspases
000126654 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aGTP Phosphohydrolases
000126654 650_7 $$0EC 3.6.5.5$$2NLM Chemicals$$aDNM1L protein, human
000126654 7001_ $$0P:(DE-HGF)0$$aBrady, Nathan Ryan$$b1$$eLast author
000126654 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.M115.643064$$gVol. 290, no. 36, p. 22005 - 22018$$n36$$p22005 - 22018$$tThe journal of biological chemistry$$v290$$x1083-351X$$y2015
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000126654 9141_ $$y2015
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