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@ARTICLE{HamacherBrady:126654,
      author       = {A. Hamacher-Brady$^*$ and N. R. Brady$^*$},
      title        = {{B}ax/{B}ak-dependent, {D}rp1-independent {T}argeting of
                      {X}-linked {I}nhibitor of {A}poptosis {P}rotein ({XIAP})
                      into {I}nner {M}itochondrial {C}ompartments {C}ounteracts
                      {S}mac/{DIABLO}-dependent {E}ffector {C}aspase
                      {A}ctivation.},
      journal      = {The journal of biological chemistry},
      volume       = {290},
      number       = {36},
      issn         = {1083-351X},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {DKFZ-2017-02682},
      pages        = {22005 - 22018},
      year         = {2015},
      abstract     = {Efficient 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.},
      keywords     = {DIABLO protein, human (NLM Chemicals) / Intracellular
                      Signaling Peptides and Proteins (NLM Chemicals) /
                      Microtubule-Associated Proteins (NLM Chemicals) /
                      Mitochondrial Proteins (NLM Chemicals) / X-Linked Inhibitor
                      of Apoptosis Protein (NLM Chemicals) / bcl-2 Homologous
                      Antagonist-Killer Protein (NLM Chemicals) / bcl-2-Associated
                      X Protein (NLM Chemicals) / Carbonyl Cyanide m-Chlorophenyl
                      Hydrazone (NLM Chemicals) / Cytochromes c (NLM Chemicals) /
                      Caspases (NLM Chemicals) / GTP Phosphohydrolases (NLM
                      Chemicals) / DNM1L protein, human (NLM Chemicals)},
      cin          = {B190},
      ddc          = {570},
      cid          = {I:(DE-He78)B190-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26134559},
      pmc          = {pmc:PMC4571954},
      doi          = {10.1074/jbc.M115.643064},
      url          = {https://inrepo02.dkfz.de/record/126654},
}