BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages
BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages
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DOI：
10.1016/j.celrep.2018.10.087
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发表时间：
2018-11-27
期刊：
影响因子：
8.8
通讯作者：
Hornung, Veit
中科院分区：
文献类型：
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作者：
Chauhan, Dhruv;Bartok, Eva;Hornung, Veit
IL-1 β是一种对炎症反应的协调至关重要的细胞因子。作为一种无活性的前细胞因子合成，IL-1 β需要蛋白水解成熟以获得生物活性。在这里，我们确定内在的细胞凋亡作为一个非典型的触发器IL-1 β成熟。通过发现从粘细菌中分离的环肽类化合物vioprolides的免疫调节活性，我们观察到IL-1 β成熟独立于典型炎性体途径，但依赖于内在凋亡。从机制上讲，vioprolides抑制MCL-1和BCL 2，进而触发BAX/BAK依赖性线粒体外膜透化（MOMP）。MOMP的诱导导致促凋亡因子的释放，引发内在凋亡，以及IAP（凋亡蛋白的抑制剂）的耗尽。IAP耗竭反过来在核糖体复合物形成的上游起作用，随后导致半胱天冬酶-8依赖性IL-1 β成熟。这些结果确立了ripoptosome/caspase-8复合物作为感测线粒体完整性扰动的促炎检查点。
IL-1 beta is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1 beta requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1 beta maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1 beta maturation independent of canonical inflammasome pathways, yet dependent on intrinsic apoptosis. Mechanistically, vioprolides inhibit MCL-1 and BCL2, which in turn triggers BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Induction of MOMP results in the release of pro-apoptotic factors initiating intrinsic apoptosis, as well as the depletion of IAPs (inhibitors of apoptosis proteins). IAP depletion, in turn, operates upstream of ripoptosome complex formation, subsequently resulting in caspase-8-dependent IL-1 beta maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity.