Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase
Intramitochondrial recruitment of endolysosomes mediates Smac degradation and constitutes a novel intrinsic apoptosis antagonizing function of XIAP E3 ligase
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DOI：
10.1038/cdd.2014.101
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发表时间：
2014-12-01
影响因子：
12.4
通讯作者：
Brady, N. R.
中科院分区：
文献类型：
--
作者：
Hamacher-Brady, A.;Choe, S. C.;Brady, N. R.
内源性细胞凋亡涉及BH3蛋白激活Bax/Bak介导的线粒体外膜通透性(MOMP)。因此，细胞色素c从线粒体中释放出来激活caspase，而Smac(线粒体衍生的第二激活剂)则抑制XIAP介导的caspase抑制。功能失调的线粒体可以通过自噬(有丝分裂)或直接通过线粒体衍生的囊泡运输来针对溶酶体降解。然而，自噬和溶酶体与凋亡线粒体相互作用的程度在很大程度上仍不清楚。在这里，我们描述了一种新的线粒体内溶酶体加工途径，该途径被规范的BH3-Only蛋白和线粒体去极化所激活。我们报告了规范的BH3-Only蛋白，TbID，Bim(EL)，Bik，Bad，和非典型BH3-Only蛋白的有丝分裂受体突变体Bnip3和Bnip3L/Nix的表达，导致内溶酶体以一种独立于有丝分裂的方式重新定位到线粒体内部隔室。作为上游调节因子，我们发现了XIAP E3连接酶。作为对线粒体去极化的反应，XIAP激活Bax介导的MOMP，即使在没有BH3-Only蛋白信号的情况下也是如此。随后，XIAP以E3连接酶依赖的方式迅速定位于所有线粒体内，XIAP介导的线粒体泛素化催化Rab膜靶向成分Rabx-5和Rep-1(RFP标记的Rab护送蛋白-1)与Rab5和Rab7阳性的内溶酶体在线粒体膜上和线粒体内的相互作用。虽然XIAP介导的MOMP允许延迟细胞色素c的释放，但在线粒体内，XIAP选择性地发出其抑制物Smac与溶酶体和蛋白酶体相关的降解信号。这些发现提示了Smac通过线粒体内降解降低线粒体凋亡潜能的一般机制。
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, Bim(EL), 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.