Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB.
Siva-1 promotes K-48 polyubiquitination of TRAF2 and inhibits TCR-mediated activation of NF-kappaB.
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DOI：
10.1615/jenvironpatholtoxicoloncol.v28.i1.30
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Kanteti P
中科院分区：
文献类型：
--
作者：
Gudi R;Barkinge J;Hawkins S;Prabhakar B;Kanteti P
促凋亡蛋白Siva-1在癌细胞的一些外在和内在凋亡信号通路中起重要作用。以前，我们发现Siva-1抑制了促生存转录因子NF-κB的活性。在本研究中，在Jurkat T白血病细胞的TCR交联后，我们证明了Siva-1的抑制靶点是NF-κB信号通路中IKK复合物的上游。此外，Siva-1还抑制了另一个关键转录因子AP-1的活性，这两种途径的共同介质是衔接蛋白TRAF 2。此外，我们观察到Siva-1确实与TRAF 2相互作用，并通过促进K48连接的多聚泛素化来负调节其活性。Siva-1与TRAF 2的环指结构域特异性相互作用，这对其E3连接酶活性及其随后激活NF-κB的能力至关重要。缺乏Siva-1的Jurkat T细胞的TCR交联显示，在TCR交联后，K48-泛素化TRAF 2水平显著降低，但K63-泛素化TRAF 2水平升高，表明这些细胞中泛素化的差异模式基本上有助于NF-κB的稳健和持续活化。上述结果证明了内源性Siva-1通过靶向TRAF 2在负调节NF-κB活化中的重要作用。
The proapoptotic protein Siva-1 plays an important role in some of the extrinsic and intrinsic apoptosis signaling pathways in cancer cells. Previously, we showed that Siva-1 inhibited the activity of the prosurvival transcription factor NF-κB. In the present study, upon TCR cross-linking of Jurkat T leukemia cells, we demonstrated that the inhibitory target of Siva-1 is upstream of the IKK complex in the NF-κB signaling pathway. Additionally, Siva-1 also suppressed the activity of another crucial transcription factor AP-1, and a common mediator of both these pathways is the adaptor protein TRAF2. Further, we observed that Siva-1 indeed interacted with TRAF2 and negatively regulated its activity by promoting K48-linked polyubiquitination. Siva-1 specifically interacted with the ring finger domain of TRAF2, which is essential for its E3 ligase activity and its ability to subsequently activate NF-κB. TCR cross-linking of Jurkat T cells that lacked Siva-1 revealed significantly lowered K48- but elevated K63-ubiquitinated TRAF2 levels upon TCR cross-linking, suggesting that the differential pattern of ubiquitination in these cells essentially contributed to a robust and sustained activation of NF-κB. The above results demonstrated an important role for endogenous Siva-1 in negatively regulating NF-κB activation by targeting TRAF2.
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