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| Home > Publications database > Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase. > print |
| Home > Publications database > Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase. > print |
| 001 | 120181 | ||
| 005 | 20240303002329.0 | ||
| 024 | 7 | _ | |a 10.1038/cdd.2014.101 |2 doi |
| 024 | 7 | _ | |a pmid:25080938 |2 pmid |
| 024 | 7 | _ | |a pmc:PMC4227142 |2 pmc |
| 024 | 7 | _ | |a 1350-9047 |2 ISSN |
| 024 | 7 | _ | |a 1476-5403 |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2017-00763 |
| 041 | _ | _ | |a eng |
| 082 | _ | _ | |a 570 |
| 100 | 1 | _ | |a Hamacher-Brady, A. |0 P:(DE-HGF)0 |b 0 |e First author |
| 245 | _ | _ | |a Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase. |
| 260 | _ | _ | |a Houndmills, Basingstoke |c 2014 |b Nature Publishing Group |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1491467457_28695 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a Intrinsic 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. |
| 536 | _ | _ | |a 312 - Functional and structural genomics (POF3-312) |0 G:(DE-HGF)POF3-312 |c POF3-312 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a DIABLO protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a Mitochondrial Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a X-Linked Inhibitor of Apoptosis Protein |2 NLM Chemicals |
| 650 | _ | 7 | |a XIAP protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Ubiquitin-Protein Ligases |0 EC 2.3.2.27 |2 NLM Chemicals |
| 650 | _ | 7 | |a parkin protein |0 EC 2.3.2.27 |2 NLM Chemicals |
| 700 | 1 | _ | |a Choe, S. C. |0 P:(DE-HGF)0 |b 1 |
| 700 | 1 | _ | |a Krijnse-Locker, J. |b 2 |
| 700 | 1 | _ | |a Brady, Nathan |0 P:(DE-He78)5bf984e94f0a31773a103cd293e01f92 |b 3 |e Last author |u dkfz |
| 773 | _ | _ | |a 10.1038/cdd.2014.101 |g Vol. 21, no. 12, p. 1862 - 1876 |0 PERI:(DE-600)1496681-5 |n 12 |p 1862 - 1876 |t Cell death and differentiation |v 21 |y 2014 |x 1476-5403 |
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