Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
Optineurin is required for CYLD-dependent inhibition of TNFα-induced NF-κB activation.
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DOI：
10.1371/journal.pone.0017477
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发表时间：
2011-03-07
期刊：
影响因子：
3.7
通讯作者：
Swarup G
中科院分区：
文献类型：
--
作者：
Nagabhushana A;Bansal M;Swarup G
核因子κ B（NF-κB）调节在多种细胞过程如炎症、免疫和细胞存活中起作用的基因。NF-κB的激活受到严格控制，去遍在蛋白酶CYLD已成为NF-κB信号传导的关键负调节因子。视神经磷酸酶在某些脑胶质瘤和肌萎缩侧索硬化中突变，也是NF-κB激活的负调节因子。它与NEMO（NF-κB必需调节剂）竞争结合泛素化RIP（受体相互作用蛋白）以阻止NF-κB活化。最近，我们确定CYLD视神经磷酸酶相互作用蛋白。本文分析了视神经磷酸酶与CYLD相互作用的功能意义。我们的研究结果表明，一种与肿瘤相关的视神经磷酸酶突变体H486 R在与CYLD的相互作用中发生了改变。与野生型视神经磷酸酶不同，H486 R突变体不能抑制肿瘤坏死因子α（TNFα）诱导的NF-κB活化。CYLD介导的对TNFα诱导的NF-κB活化的抑制作用被H486 R突变体的表达所消除。敲低视神经磷酸酶后，CYLD不能抑制TNFα诱导的NF-κB活化，并显示与泛素化RIP的相互作用显著降低。在视神经磷酸酶敲低的细胞中，泛素化RIP的水平增加。在视神经磷酸酶敲低细胞中，过度表达CYLD导致RIP去泛素化被废除。这些结果表明，视神经磷酸酶通过介导CYLD与泛素化RIP的相互作用，从而促进RIP的去泛素化，从而调节NF-κB活化。
The nuclear factor kappa B (NF-κB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-κB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-κB signalling. Optineurin, mutated in certain glaucomas and amyotrophic lateral sclerosis, is also a negative regulator of NF-κB activation. It competes with NEMO (NF-κB essential modulator) for binding to ubiquitinated RIP (receptor interacting protein) to prevent NF-κB activation. Recently we identified CYLD as optineurin-interacting protein. Here we have analysed the functional significance of interaction of optineurin with CYLD. Our results show that a glaucoma-associated mutant of optineurin, H486R, is altered in its interaction with CYLD. Unlike wild-type optineurin, the H486R mutant did not inhibit tumour necrosis factor α (TNFα)-induced NF-κB activation. CYLD mediated inhibition of TNFα-induced NF-κB activation was abrogated by expression of the H486R mutant. Upon knockdown of optineurin, CYLD was unable to inhibit TNFα-induced NF-κB activation and showed drastically reduced interaction with ubiquitinated RIP. The level of ubiquitinated RIP was increased in optineurin knockdown cells. Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells. These results suggest that optineurin regulates NF-κB activation by mediating interaction of CYLD with ubiquitinated RIP thus facilitating deubiquitination of RIP.
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