Optineurin Negatively Regulates TNFα- Induced NF-κB Activation by Competing with NEMO for Ubiquitinated RIP
Optineurin Negatively Regulates TNFα- Induced NF-κB Activation by Competing with NEMO for Ubiquitinated RIP
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DOI：
10.1016/j.cub.2007.07.041
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发表时间：
2007-08
期刊：
影响因子：
9.2
通讯作者：
Guozhi Zhu;Chuan-Jin Wu;Yongge Zhao;J. Ashwell
中科院分区：
文献类型：
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作者：
Guozhi Zhu;Chuan-Jin Wu;Yongge Zhao;J. Ashwell
核因子-κB基本调节剂(NEMO)是I-κB激酶(IKK)的调节亚基，激活核因子-κB，对核因子-κB的激活至关重要[1]。最近发现NEMO包含一个区域，该区域优先与Lys(K)63连接而不是K48连接的多泛素(PolyUb)链结合，并且Nemo与K63连接的PolyUb RIP(受体相互作用蛋白)结合的能力是肿瘤坏死因子α(TNFα)有效诱导NF-κB激活所必需的[2，3]。视神经磷酸酶是NEMO的同系物，在青光眼患者中发现了视神经磷酸酶基因的突变[4]，青光眼是一种涉及视网膜神经节细胞丢失的神经退行性疾病[5]。尽管Optineurin与NEMO有相当大的同源性，但在静息细胞中，它不存在于包含IKKα和IKKβ的高分子复合体中，并且在内毒素诱导的NF-κB激活中，Optineurin不能取代NEMO[6]。另一方面，Optineurin的过表达阻断了E3-14.7K对肿瘤坏死因子α受体1过表达引起的细胞死亡的保护作用[7]。在这里，我们证明了optineurin具有一个与Nemo类似的K63连接的PolyUb结合区，并且像Nemo一样，它结合了K63-而不是K48连接的PolyUb。Optineurin竞争性拮抗NEMO与PolyUb RIP的结合，其过表达抑制肿瘤坏死因子α诱导的NF-κB活化。这种竞争发生在生理蛋白水平，因为Optineurin的MicroRNA沉默导致明显增强了肿瘤坏死因子α诱导的NF-κB活性。这些结果揭示了视神经磷酸酶在抑制肿瘤坏死因子α信号转导中的生理作用，这一作用可能为其与青光眼的相关性提供了解释。
NF-κB essential modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) that activates NF-κB, is essential for NF-κB activation [1]. NEMO was recently found to contain a region that preferentially binds Lys (K)63-linked but not K48-linked polyubiquitin (polyUb) chains, and the ability of NEMO to bind to K63-linked polyUb RIP (receptor-interacting protein) is necessary for efficient tumor necrosis factor α (TNFα)-induced NF-κB activation [2, 3]. Optineurin is a homolog of NEMO, and mutations in theoptineuringene are found in a subset of patients with glaucoma [4], a neurodegenerative disease involving the loss of retinal ganglion cells [5]. Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKKα and IKKβ, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-κB activation [6]. On the other hand, the overexpression of optineurin blocks the protective effect of E3-14.7K on cell death caused by the overexpression of TNFα receptor 1 (TNFR1) [7]. Here we show that optineurin has a K63-linked polyUb-binding region similar to that of NEMO, and like NEMO, it bound K63- but not K48-linked polyUb. Optineurin competitively antagonized NEMO's binding to polyUb RIP, and its overexpression inhibited TNFα-induced NF-κB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNFα-induced NF-κB activity. These results reveal a physiologic role for optineurin in dampening TNFα signaling, and this role might provide an explanation for its association with glaucoma.