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@ARTICLE{HamacherBrady:120181,
      author       = {A. Hamacher-Brady$^*$ and S. C. Choe$^*$ and J.
                      Krijnse-Locker and N. Brady$^*$},
      title        = {{I}ntramitochondrial recruitment of endolysosomes mediates
                      {S}mac degradation and constitutes a novel intrinsic
                      apoptosis antagonizing function of {XIAP} {E}3 ligase.},
      journal      = {Cell death and differentiation},
      volume       = {21},
      number       = {12},
      issn         = {1476-5403},
      address      = {Houndmills, Basingstoke},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2017-00763},
      pages        = {1862 - 1876},
      year         = {2014},
      abstract     = {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.},
      keywords     = {DIABLO protein, human (NLM Chemicals) / Intracellular
                      Signaling Peptides and Proteins (NLM Chemicals) /
                      Mitochondrial Proteins (NLM Chemicals) / X-Linked Inhibitor
                      of Apoptosis Protein (NLM Chemicals) / XIAP protein, human
                      (NLM Chemicals) / Ubiquitin-Protein Ligases (NLM Chemicals)
                      / parkin protein (NLM Chemicals)},
      cin          = {B190 / B170},
      ddc          = {570},
      cid          = {I:(DE-He78)B190-20160331 / I:(DE-He78)B170-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25080938},
      pmc          = {pmc:PMC4227142},
      doi          = {10.1038/cdd.2014.101},
      url          = {https://inrepo02.dkfz.de/record/120181},
}