Ubiquitylation of an internalized killer cell Ig-like receptor by Triad3A disrupts sustained NF-κB signaling.
Ubiquitylation of an internalized killer cell Ig-like receptor by Triad3A disrupts sustained NF-κB signaling.
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DOI：
10.4049/jimmunol.1000112
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发表时间：
2011-03-01
期刊：
影响因子：
--
通讯作者：
Campbell KS
中科院分区：
文献类型：
--
作者：
Miah SM;Purdy AK;Rodin NB;MacFarlane AW 4th;Oshinsky J;Alvarez-Arias DA;Campbell KS
KIR 2DL 4（2DL 4，CD 158 d）是一种表达于人NK细胞上的独特的杀伤细胞Ig样受体（KIR），可刺激细胞因子的产生，但其表达和功能的调控机制尚不清楚。通过酵母双杂交筛选，我们确定了E3泛素连接酶，Triad 3A，作为2DL 4胞质结构域的相互作用伴侣。在体内证实了蛋白质相互作用，并且Triad 3A表达诱导了2DL 4的多聚泛素化和降解。Triad 3A的过表达选择性地废除了2DL 4的精氨酸产生功能，而Triad 3A shRNA逆转了泛素化并恢复了细胞因子的产生。在NK细胞系中Triad 3A的表达不影响受体表面表达、内化或早期信号传导，但显著降低受体转换并抑制持续的NF-κB活化。发现2DL 4内吞作用对于刺激细胞因子产生至关重要，并且Triad 3A表达减少了早期内体中内化受体的定位。我们的研究结果揭示了内吞的2DL 4受体在产生持续的NF-κB信号和驱动细胞因子产生中的关键作用。我们的结论是，Triad 3A是一个关键的负调节持续的2DL 4介导的NF-κB信号转导从内化的2DL 4，其功能通过促进泛素化和降解的内吞受体从早期内涵体。“这是一个作者制作的版本的手稿接受发表在免疫学杂志（JI）。美国免疫学家协会(AAI)JI的出版商拥有本手稿的版权。这一版本的手稿尚未由联合执行进行复制编辑或编辑校对;因此，它可能与联合执行发表的最后版本（在线和印刷版）不同。AAI（JI）对作者制作的手稿版本或美国国立卫生研究院或任何其他第三方从中衍生的任何版本中的错误或遗漏不承担责任。记录的最后可引用版本可在www.jimmunol.org上找到。”
KIR2DL4 (2DL4, CD158d) is a unique killer cell Ig-like receptor (KIR) expressed on human NK cells, which stimulates cytokine production, but mechanisms regulating its expression and function are poorly understood. By yeast two-hybrid screening, we identified the E3 ubiquitin ligase, Triad3A, as an interaction partner for the 2DL4 cytoplasmic domain. The protein interaction was confirmed in vivo, and Triad3A expression induced polyubiquitylation and degradation of 2DL4. Overexpression of Triad3A selectively abrogated cytokine-producing function of 2DL4, while Triad3A shRNA reversed ubiquitylation and restored cytokine production. Expression of Triad3A in an NK cell line did not affect receptor surface expression, internalization, or early signaling, but significantly reduced receptor turnover and suppressed sustained NF-κB activation. 2DL4 endocytosis was found to be vital to stimulate cytokine production, and Triad3A expression diminished localization of internalized receptor in early endosomes. Our results reveal a critical role for endocytosed 2DL4 receptor to generate sustained NF-κB signaling and drive cytokine production. We conclude that Triad3A is a key negative regulator of sustained 2DL4-mediated NF-κB signaling from internalized 2DL4, which functions by promoting ubiquitylation and degradation of endocytosed receptor from early endosomes. “This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final, citable version of record can be found at www.jimmunol.org.”
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