Rhomboid domain-containing protein 3 is a negative regulator of TLR3-triggered natural killer cell activation
Rhomboid domain-containing protein 3 is a negative regulator of TLR3-triggered natural killer cell activation
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含菱形结构域的蛋白 3 是 TLR3 触发的自然杀伤细胞激活的负调节因子
DOI：
10.1073/pnas.1220466110
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发表时间：
2013-05-07
影响因子：
11.1
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Liu, Juan;Liu, Shuxun;Cao, Xuetao
Rhomboid domain containing protein 3（Rhbdd 3）是一类在免疫细胞中广泛表达的蛋白质家族，其在免疫中的作用尚不清楚。自然杀伤（NK）细胞对宿主免疫防御至关重要，也可以介导炎症性疾病，如肝炎。尽管对NK细胞如何被激活已经有了很多了解，但NK细胞激活的负调控的详细机制仍有待充分理解。使用Rhbdd 3缺陷型小鼠，我们发现，Rhbdd 3，选择性上调Toll样受体3（TLR 3）刺激后，在NK细胞中，负调控TLR 3介导的NK细胞活化的反馈方式。Rhbdd 3抑制TLR 3触发的NK细胞IFN-γ和颗粒酶B的表达，在辅助细胞如树突状细胞和枯否细胞的细胞-细胞接触依赖性中。Rhbdd 3与12 kDa的DNAX活化蛋白相互作用并促进其降解，抑制TLR 3触发的NK细胞中的MAPK活化。此外，Rhbdd 3通过控制NK细胞在肝脏中的活化和积累以及破坏NK细胞-枯否细胞相互作用，在减轻TLR 3触发的急性炎症中起关键作用。因此，Rhbdd 3是TLR 3触发的NK细胞活化的反馈抑制剂。我们的研究概述了NK细胞活化的负调控机制，也为菱形蛋白在免疫中的功能提供了线索。
Rhomboid domain-containing protein 3 (Rhbdd3), which belongs to a family of proteins with rhomboid domain, is widely expressed in immune cells; however, the roles of the Rhbdd members, including Rhbdd3, in immunity remain unknown. Natural killer (NK) cells are critical for host immune defense and also can mediate inflammatory diseases such as hepatitis. Although much is known about how NK cells are activated, the detailed mechanisms for negative regulation of NK cell activation remain to be fully understood. Using Rhbdd3-deficient mice, we reveal that Rhbdd3, selectively up-regulated in NK cells upon Toll-like receptor 3 (TLR3) stimulation, negatively regulates TLR3-mediated NK cell activation in a feedback manner. Rhbdd3 inhibits TLR3-triggered IFN-γ and granzyme B expression of NK cells in cell–cell contact dependence of accessory cells such as dendritic cells and Kupffer cells. Rhbdd3 interacts with DNAX activation protein of 12 kDa and promotes its degradation, inhibiting MAPK activation in TLR3-triggered NK cells. Furthermore, Rhbdd3 plays a critical role in attenuating TLR3-triggered acute inflammation by controlling NK cell activation and accumulation in liver and disrupting NK cell–Kupffer cell interaction. Therefore, Rhbdd3 is a feedback inhibitor of TLR3-triggered NK cell activation. Our study outlines a mechanism for the negative regulation of NK cell activation and also provides clues for the function of the rhomboid proteins in immunity.