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000120181 0247_ $$2doi$$a10.1038/cdd.2014.101
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000120181 037__ $$aDKFZ-2017-00763
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000120181 1001_ $$0P:(DE-HGF)0$$aHamacher-Brady, A.$$b0$$eFirst author
000120181 245__ $$aIntramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase.
000120181 260__ $$aHoundmills, Basingstoke$$bNature Publishing Group$$c2014
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000120181 520__ $$aIntrinsic apoptosis involves BH3-only protein activation of Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Consequently, cytochrome c is released from the mitochondria to activate caspases, and Smac (second mitochondria-derived activator of caspases) to inhibit XIAP-mediated caspase suppression. Dysfunctional mitochondria can be targeted for lysosomal degradation via autophagy (mitophagy), or directly through mitochondria-derived vesicle transport. However, the extent of autophagy and lysosomal interactions with apoptotic mitochondria remains largely unknown. We describe here a novel pathway of endolysosomal processing of mitochondria, activated in response to canonical BH3-only proteins and mitochondrial depolarization. We report that expression of canonical BH3-only proteins, tBid, BimEL, Bik, Bad, and mitophagy receptor mutants of atypical BH3-only proteins, Bnip3 and Bnip3L/Nix, leads to prominent relocalization of endolysosomes into inner mitochondrial compartments, in a manner independent of mitophagy. As an upstream regulator, we identified the XIAP E3 ligase. In response to mitochondrial depolarization, XIAP actuates Bax-mediated MOMP, even in the absence of BH3-only protein signaling. Subsequently, in an E3 ligase-dependent manner, XIAP rapidly localizes inside all the mitochondria, and XIAP-mediated mitochondrial ubiquitylation catalyses interactions of Rab membrane targeting components Rabex-5 and Rep-1 (RFP-tagged Rab escort protein-1), and Rab5- and Rab7-positive endolysosomes, at and within mitochondrial membrane compartments. While XIAP-mediated MOMP permits delayed cytochrome c release, within the mitochondria XIAP selectively signals lysosome- and proteasome-associated degradation of its inhibitor Smac. These findings suggest a general mechanism to lower the mitochondrial apoptotic potential via intramitochondrial degradation of Smac.
000120181 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000120181 650_7 $$2NLM Chemicals$$aDIABLO protein, human
000120181 650_7 $$2NLM Chemicals$$aIntracellular Signaling Peptides and Proteins
000120181 650_7 $$2NLM Chemicals$$aMitochondrial Proteins
000120181 650_7 $$2NLM Chemicals$$aX-Linked Inhibitor of Apoptosis Protein
000120181 650_7 $$2NLM Chemicals$$aXIAP protein, human
000120181 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000120181 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aparkin protein
000120181 7001_ $$0P:(DE-HGF)0$$aChoe, S. C.$$b1
000120181 7001_ $$aKrijnse-Locker, J.$$b2
000120181 7001_ $$0P:(DE-He78)5bf984e94f0a31773a103cd293e01f92$$aBrady, Nathan$$b3$$eLast author$$udkfz
000120181 773__ $$0PERI:(DE-600)1496681-5$$a10.1038/cdd.2014.101$$gVol. 21, no. 12, p. 1862 - 1876$$n12$$p1862 - 1876$$tCell death and differentiation$$v21$$x1476-5403$$y2014
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