CLIPR-59 regulates TNF-α-induced apoptosis by controlling ubiquitination of RIP1.
CLIPR-59 regulates TNF-α-induced apoptosis by controlling ubiquitination of RIP1.
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DOI：
10.1038/cddis.2012.3
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发表时间：
2012-02-02
影响因子：
9
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中科院分区：
文献类型：
--
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肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）通过调节细胞凋亡和细胞因子基因的转录激活，在多种免疫事件中发挥重要作用。由1型肿瘤坏死因子受体（TNFR 1）介导的细胞内信号传导由两个连续的蛋白质复合物构成：含有受体的复合物-I和含有胱天蛋白酶-8的复合物-II。蛋白质修饰，特别是泛素化，与这些复合物的形成的调节有关。然而，基本的机制仍然不明确。在这里，我们确定了CLIP-170相关的59 kDa蛋白（CLIPR-59）作为一种新的衔接蛋白TNFR 1。CLIPR-59水平的实验性降低阻止了TNF-α信号传导背景下的细胞凋亡诱导和半胱天冬酶激活。CLIPR-59结合TNFR 1，但响应于TNF-α刺激而解离。然而，CLIPR-59也参与并需要复合物-II的形成。此外，CLIPR-59通过与去泛素化酶CYLD的结合调节TNF-α诱导的受体相互作用蛋白1（RIP 1）的泛素化。这些发现表明，CLIPR-59调节RIP 1的泛素化，导致复合物II的形成，从而促进Caspase-8活化以诱导TNF-α的凋亡。
Tumor necrosis factor-α (TNF-α) has important roles in several immunological events by regulating apoptosis and transcriptional activation of cytokine genes. Intracellular signaling mediated by TNF-receptor-type 1 (TNFR1) is constituted by two sequential protein complexes: Complex-I containing the receptor and Complex-II-containing Caspase-8. Protein modifications, particularly ubiquitination, are associated with the regulation of the formation of these complexes. However, the underlying mechanisms remain poorly defined. Here, we identified CLIP-170-related 59 kDa protein (CLIPR-59) as a novel adaptor protein for TNFR1. Experimental reduction of CLIPR-59 levels prevented induction of apoptosis and activation of caspases in the context of TNF-α signaling. CLIPR-59 binds TNFR1 but dissociates in response to TNF-α stimulation. However, CLIPR-59 is also involved in and needed for the formation of Complex-II. Moreover, CLIPR-59 regulates TNF-α-induced ubiquitination of receptor-interacting protein 1 (RIP1) by its association with CYLD, a de-ubiquitinating enzyme. These findings suggest that CLIPR-59 modulates ubiquitination of RIP1, resulting in the formation of Complex-II and thus promoting Caspase-8 activation to induce apoptosis by TNF-α.
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