Inducible turnover of optineurin regulates T cell activation.
Inducible turnover of optineurin regulates T cell activation.
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DOI：
10.1016/j.molimm.2017.01.027
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发表时间：
2017-05
影响因子：
3.6
通讯作者：
Kane LP
中科院分区：
文献类型：
--
作者：
Montecalvo A;Watkins SC;Orange J;Kane LP
视神经磷酸酶（Optn）是与IκB激酶（IKK）复合物的调节亚基NF-κB必需调节因子（NEMO）同源的衔接蛋白。Optn的失调与神经退行性疾病、自身免疫性疾病和骨疾病有关。Optn与NEMO具有高度同源性，但不是含有IKKα和IKKβ的相同高分子量复合物的一部分。尽管它与NEMO同源，并且事实上它已经成为几种细胞类型中广泛研究的主题，但没有发表的研究解决了Optn在T细胞活化过程中的作用。在这里，我们证明Optn的异位表达下调TCR诱导的NF-κB活化和TNF-α的产生，其方式依赖于泛素结合。相反，Optn的敲低增强NF-κB活化和TNF-α的产生。与该蛋白的负调节作用一致，我们在两种细胞系和原代鼠T细胞中观察到TCR刺激后Optn的瞬时损失。Optn的急性损失似乎是由于蛋白质降解和胞吐作用，后者通过激活诱导的外泌体。因此，这项研究提供了关于Optn在TCR活化过程中的作用的新信息，表明Optn在炎症和/或自身免疫性疾病中可能的重要性。
Optineurin (Optn) is an adaptor protein with homology to NF-κB essential-modulator (NEMO), the regulatory subunit of the IκB kinase (IKK) complex. Dysregulation of Optn has been linked to neurodegenerative, autoimmune and bone diseases. Optn shares a high degree of homology with NEMO, but is not part of the same high-molecular weight complex containing IKKα and IKKβ. Despite its homology with NEMO and the fact that it has been the subject of extensive study in several cell types, there are no published studies addressing the role of Optn during T cell activation. Here we demonstrate that ectopic expression of Optn down-regulates TCR- induced NF-κB activation and TNF-α production, in a manner dependent on ubiquitin-binding. Conversely, knock-down of Optn enhances NF-κB activation and the production of TNF-α. Consistent with a negative regulatory role for this protein, we observed transient loss of Optn after TCR stimulation in both cell lines and in primary murine T cells. The acute loss of Optn appears to be due to both protein degradation and exocytosis, the latter via activation-induced exosomes. This study therefore provides novel information regarding the role of Optn during TCR activation, suggesting the possible importance of Optn during inflammation and/or autoimmune diseases.