Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform.
Ubiquitin-like modifier FAT10 attenuates RIG-I mediated antiviral signaling by segregating activated RIG-I from its signaling platform.
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DOI：
10.1038/srep23377
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发表时间：
2016-03-21
影响因子：
4.6
通讯作者：
Yoo JY
中科院分区：
文献类型：
--
作者：
Nguyen NT;Now H;Kim WJ;Kim N;Yoo JY
RIG-I 是一种关键的胞质 RNA 传感器，可介导针对 RNA 病毒的先天免疫防御。 RIG-I 活性异常会导致严重的病理状态，例如常染色体显性多系统疾病、炎性肌病和皮肌炎。因此，识别能够确保有效防御且不产生有害免疫病理的调节因子对于应对 RIG-I 相关疾病尤为重要。在这里，我们提出了炎症诱导型 FAT10 作为 RIG-I 介导的炎症反应的新型负调节因子。在各种细胞系中，FAT10 蛋白是检测不到的，除非它是由促炎细胞因子诱导的。 FAT10 与 RIG-I 的 2CARD 结构域非共价结合，并通过调节 RIG-I 蛋白溶解度来抑制病毒 RNA 诱导的 IRF3 和 NF-kB 激活。我们进一步证明FAT10被招募到RIG-I-TRIM25中形成抑制复合物，其中FAT10被E3连接酶TRIM25稳定。结果，FAT10 抑制了含有 RIG-I 的抗病毒应激颗粒的形成，并将活性 RIG-I 与线粒体隔离。我们的研究提出了一种抑制 RIG-I 活性的新机制。在具有促炎症环境的各种癌症中观察到高度积累的FAT10，因此，我们的发现揭示了积累的FAT10在病毒介导的炎症反应期间的抑制作用，也可能为理解与感染和炎症相关的癌发生提供分子线索。
RIG-I is a key cytosolic RNA sensor that mediates innate immune defense against RNA virus. Aberrant RIG-I activity leads to severe pathological states such as autosomal dominant multi-system disorder, inflammatory myophathies and dermatomyositis. Therefore, identification of regulators that ensure efficient defense without harmful immune-pathology is particularly critical to deal with RIG-I-associated diseases. Here, we presented the inflammatory inducible FAT10 as a novel negative regulator of RIG-I-mediated inflammatory response. In various cell lines, FAT10 protein is undetectable unless it is induced by pro-inflammatory cytokines. FAT10 non-covalently associated with the 2CARD domain of RIG-I, and inhibited viral RNA-induced IRF3 and NF-kB activation through modulating the RIG-I protein solubility. We further demonstrated that FAT10 was recruited to RIG-I-TRIM25 to form an inhibitory complex where FAT10 was stabilized by E3 ligase TRIM25. As the result, FAT10 inhibited the antiviral stress granules formation contains RIG-I and sequestered the active RIG-I away from the mitochondria. Our study presented a novel mechanism to dampen RIG-I activity. Highly accumulated FAT10 is observed in various cancers with pro-inflammatory environment, therefore, our finding which uncovered the suppressive effect of the accumulated FAT10 during virus-mediated inflammatory response may also provide molecular clue to understand the carcinogenesis related with infection and inflammation.