The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis
The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis
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DOI：
10.1007/s10495-007-0164-7
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发表时间：
2008-02-01
期刊：
影响因子：
7.2
通讯作者：
Dubiel, Wolfgang
中科院分区：
文献类型：
--
作者：
Hetfeld, Bettina K. J.;Peth, Andreas;Dubiel, Wolfgang
与泛素（Ub）蛋白酶体系统（UPS）一致，COP 9信号体（CSN）控制细胞调节剂的稳定性。CSN与cullin-RING Ub连接酶（CRL）相互作用，所述CRL由特异性cullin、RING蛋白Rbx 1和底物识别蛋白组成。Ub样蛋白Nedd 8与cullin共价连接，并通过CSN介导的去eddylation去除。neddylation和deneddylation的循环调节CRL。凋亡刺激引起UPS的半胱天冬酶依赖性修饰。然而，对细胞凋亡过程中的CSN知之甚少。我们在体外和体内证明，在抗Fas抗体或依托泊苷诱导的细胞凋亡2-3小时后，胱天蛋白酶3在D-2 - 3处最有效地切割CSN 6。CSN 6加工发生在CSN-CRL复合物中，随后是CSN 6的直接相互作用伴侣Rbx 1的切割。Rbx 1的半胱天冬酶依赖性切割伴随着Jurkat T细胞中neddylated蛋白的减少。CSN 6切割的另一个功能性结果是CSN介导的去乙酰化活性的增强，导致细胞中cullin 1的去乙酰化。CSN相关的去泛素化以及激酶活性在活性胱天蛋白酶3存在下保持不变。Rbx 1的裂解和cullin的去甲基化增加使CRLs稳定，并可能稳定最终凋亡步骤的促凋亡因子。
In concert with the ubiquitin (Ub) proteasome system (UPS) the COP9 signalosome (CSN) controls the stability of cellular regulators. The CSN interacts with cullin-RING Ub ligases (CRLs) consisting of a specific cullin, a RING protein as Rbx1 and substrate recognition proteins. The Ub-like protein Nedd8 is covalently linked to cullins and removed by the CSN-mediated deneddylation. Cycles of neddylation and deneddylation regulate CRLs. Apoptotic stimuli cause caspase-dependent modifications of the UPS. However, little is known about the CSN during apoptosis. We demonstrate in vitro and in vivo that CSN6 is cleaved most effectively by caspase 3 at D-23 after 2-3 h of apoptosis induced by anti-Fas-Ab or etoposide. CSN6 processing occurs in CSN-CRL complexes and is followed by the cleavage of Rbx1, the direct interaction partner of CSN6. Caspase-dependent cutting of Rbx1 is accompanied by decrease of neddylated proteins in Jurkat T cells. Another functional consequence of CSN6 cleavage is the enhancement of CSN-mediated deneddylating activity causing deneddylation of cullin 1 in cells. The CSN-associated deubiquitinating as well as kinase activity remained unchanged in presence of active caspase 3. The cleavage of Rbx1 and increased deneddylation of cullins inactivate CRLs and presumably stabilize pro-apoptotic factors for final apoptotic steps.