Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis.
Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis.
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DOI：
10.1038/ncomms12547
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发表时间：
2016-08-24
影响因子：
16.6
通讯作者：
Tokunaga F
中科院分区：
文献类型：
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作者：
Nakazawa S;Oikawa D;Ishii R;Ayaki T;Takahashi H;Takeda H;Ishitani R;Kamei K;Takeyoshi I;Kawakami H;Iwai K;Hatada I;Sawasaki T;Ito H;Nureki O;Tokunaga F
视神经磷酸酶（OPTN）突变导致神经退行性疾病，包括肌萎缩侧索硬化症（ALS）和青光眼。尽管据报道OPTN的UBAN结构域中ALS相关的E478 G突变消除了其NF-κB抑制活性，但ALS发病机制的精确分子基础仍不清楚。在这里，我们报告OPTN-UBAN结构域是至关重要的NF-κB抑制。我们的晶体结构分析表明，OPTN-UBAN结合线性泛素与NEMO同源。TNF-α介导的NF-κB活化在OPTN敲除细胞中通过增加泛素化和TNF受体（TNFR）复合物I组分的缔合而增强。此外，OPTN结合半胱天冬酶8，并且OPTN缺乏通过增强复合物II形成来加速TNF-α诱导的细胞凋亡。对来自OPTN相关ALS患者的运动神经元的免疫组织化学分析显示，线性泛素和活化的NF-κB与细胞质内含物部分共定位，并且半胱天冬酶的活化升高。总之，OPTN通过线性泛素结合调节NF-κB活化和细胞凋亡，这种能力的丧失可能导致ALS。 视神经磷酸酶的突变与神经退行性疾病有关，包括肌萎缩侧索硬化症。在这里，作者报道了optineurin的泛素结合结构域的结构，其结合线性泛素与NEMO同源，并探讨该结构域的功能。
Optineurin (OPTN) mutations cause neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and glaucoma. Although the ALS-associated E478G mutation in the UBAN domain of OPTN reportedly abolishes its NF-κB suppressive activity, the precise molecular basis in ALS pathogenesis still remains unclear. Here we report that the OPTN-UBAN domain is crucial for NF-κB suppression. Our crystal structure analysis reveals that OPTN-UBAN binds linear ubiquitin with homology to NEMO. TNF-α-mediated NF-κB activation is enhanced in OPTN-knockout cells, through increased ubiquitination and association of TNF receptor (TNFR) complex I components. Furthermore, OPTN binds caspase 8, and OPTN deficiency accelerates TNF-α-induced apoptosis by enhancing complex II formation. Immunohistochemical analyses of motor neurons from OPTN-associated ALS patients reveal that linear ubiquitin and activated NF-κB are partially co-localized with cytoplasmic inclusions, and that activation of caspases is elevated. Taken together, OPTN regulates both NF-κB activation and apoptosis via linear ubiquitin binding, and the loss of this ability may lead to ALS. Mutations in optineurin are associated with neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, the authors report the structure of the ubiquitin binding domain of optineurin, which binds linear ubiquitin with homology to NEMO, and explore the function of this domain.