A Krebs Cycle Component Limits Caspase Activation Rate through Mitochondrial Surface Restriction of CRL Activation
A Krebs Cycle Component Limits Caspase Activation Rate through Mitochondrial Surface Restriction of CRL Activation
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DOI：
10.1016/j.devcel.2016.02.025
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发表时间：
2016-04-04
影响因子：
11.8
通讯作者：
Arama, Eli
中科院分区：
文献类型：
--
作者：
Aram, Lior;Braun, Tslil;Arama, Eli
在caspase介导的大细胞结构的凋亡过程中，细胞如何避免过度的caspase活性和不必要的细胞死亡尚不清楚。我们研究了在精子细胞个体化过程中caspase介导的果蝇精子细胞质内容物的挤压。我们发现，克雷布斯循环组分，琥珀酰辅酶a合成酶β亚基（a - sb）的atp特异性形式，结合并激活精子中caspase激活所需的cullin -3-基泛素连接酶（CRL3）复合物。体外和体内证据表明，这种相互作用发生在线粒体表面，从而将CRL3复合物的激活源限制在该细胞器附近，并将caspase的潜在激活率降低至少60%。在克雷布斯循环中冗余发挥作用的a - sb和gtp特异性SCS β (G-S β)之间的结构域交换表明，a -s β在精子中的代谢和结构作用可以解耦，突出了该克雷布斯循环成分在CRL激活中的兼职功能。
How cells avoid excessive caspase activity and unwanted cell death during apoptotic caspase-mediated removal of large cellular structures is poorly understood. We investigate caspase-mediated extrusion of spermatid cytoplasmic contents in Drosophila during spermatid individualization. We show that a Krebs cycle component, the ATP-specific form of the succinyl-CoA synthetase beta subunit (A-Sb), binds to and activates the Cullin-3-based ubiquitin ligase (CRL3) complex required for caspase activation in spermatids. In vitro and in vivo evidence suggests that this interaction occurs on the mitochondrial surface, thereby limiting the source of CRL3 complex activation to the vicinity of this organelle and reducing the potential rate of caspase activation by at least 60%. Domain swapping between A-Sb and the GTP-specific SCS beta (G-S beta), which functions redundantly in the Krebs cycle, show that the metabolic and structural roles of A-S beta in spermatids can be uncoupled, highlighting a moonlighting function of this Krebs cycle component in CRL activation.