Siva1 is a XIAP-interacting protein that balances NFκB and JNK signalling to promote apoptosis
Siva1 is a XIAP-interacting protein that balances NFκB and JNK signalling to promote apoptosis
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DOI：
10.1242/jcs.049940
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发表时间：
2009-08-01
影响因子：
4
通讯作者：
de Martin, Rainer
中科院分区：
文献类型：
--
作者：
Resch, Ulrike;Schichl, Yvonne M.;de Martin, Rainer
XIAP被认为是一种有效的细胞凋亡抑制剂，但除此之外还参与细胞信号传导，包括NF κ B、JNK和TGF β途径。我们对XIAP相互作用伙伴的搜索使我们找到了Siva 1，这是一种促凋亡蛋白，已知其通过半胱天冬酶依赖性线粒体途径在T细胞凋亡中发挥作用。XIAP和Siva 1之间的相互作用位点被定位到XIAP的RING结构域和Siva 1的N-末端、含SAH和含死亡同源区的结构域。免疫共沉淀实验表明，XIAP，Siva 1和TAK 1在Jurkat T细胞中形成三元复合物。报告基因分析显示，Siva 1抑制XIAP和TAK 1-TAB 1介导的NF κ B活化。相反，Siva 1增加XIAP和TNF α介导的AP 1活性，延长TNF α诱导的JNK激活，而敲低Siva 1导致JNK激活减少。这表明Siva 1通过JNK和NF κ B B不同地调节信号传导，并将这些途径之间的平衡向增强的JNK活化转移，这是一种促进细胞凋亡的情况。异位表达Siva 1增加caspase-3活性，XIAP以泛素连接酶依赖的方式抑制caspase-3活性。与此一致，Siva 1是赖氨酸-48-连接的XIAP多泛素化。我们的研究结果表明，通过与XIAP和TAK 1的物理相互作用，Siva 1减少NF κ B B和增强JNK活性，有利于凋亡。
XIAP is known as a potent inhibitor of apoptosis, but in addition is involved in cellular signalling, including the NF kappa B, JNK and TGF beta pathways. Our search for XIAP-interacting partners led us to Siva1, a proapoptotic protein that is known to play a role in T-cell apoptosis through a caspase-dependent mitochondrial pathway. The interaction sites between XIAP and Siva1 were mapped to the RING domain of XIAP and the N-terminal, SAH-containing and death-homology-region-containing domains of Siva1. Co-immunoprecipitation experiments showed that XIAP, Siva1 and TAK1 form a ternary complex in Jurkat T cells. Reporter-gene analysis revealed that Siva1 inhibits XIAP-and TAK1-TAB1-mediated NF kappa B activation. By contrast, Siva1 increased XIAP- and TNF alpha-mediated AP1 activity and prolonged TNF alpha-induced JNK activation, whereas knock down of Siva1 resulted in reduced JNK activation. This suggests that Siva1 differentially modulates signalling by JNK and NF kappa B and shifts the balance between these pathways towards enhanced JNK activation, a situation that promotes apoptosis. Ectopically expressed Siva1 increased caspase-3 activity, which was inhibited by XIAP in a ubiquitin-ligase-dependent manner. In line with this, Siva1 was lysine-48-linked polyubiquitylated by XIAP. Our findings suggest that, via physical interaction with XIAP and TAK1, Siva1 diminishes NF kappa B and enhances JNK activity to favour apoptosis.