TY  - JOUR
AU  - Hamacher-Brady, A.
AU  - Choe, S. C.
AU  - Krijnse-Locker, J.
AU  - Brady, Nathan
TI  - Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase.
JO  - Cell death and differentiation
VL  - 21
IS  - 12
SN  - 1476-5403
CY  - Houndmills, Basingstoke
PB  - Nature Publishing Group
M1  - DKFZ-2017-00763
SP  - 1862 - 1876
PY  - 2014
AB  - 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.
KW  - DIABLO protein, human (NLM Chemicals)
KW  - Intracellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - Mitochondrial Proteins (NLM Chemicals)
KW  - X-Linked Inhibitor of Apoptosis Protein (NLM Chemicals)
KW  - XIAP protein, human (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - parkin protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25080938
C2  - pmc:PMC4227142
DO  - DOI:10.1038/cdd.2014.101
UR  - https://inrepo02.dkfz.de/record/120181
ER  -