USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling.
USP15 Deubiquitinates CARD9 to Downregulate C-Type Lectin Receptor-Mediated Signaling.
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DOI：
10.4049/immunohorizons.2000036
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发表时间：
2020-10-22
期刊：
影响因子：
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通讯作者：
Xavier RJ
中科院分区：
文献类型：
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作者：
Xu W;Rush JS;Graham DB;Cao Z;Xavier RJ
翻译后修饰是快速调节蛋白质功能以响应刺激的有效手段。尽管泛素化事件和涉及的E3泛素连接酶在许多信号通路中的特征越来越多，但它们通过去泛素化酶进行的调控仍然知之甚少。C型凝集素受体(CLR)信号转接子CARD9先前被报道通过TRIM62介导的泛素化被激活。在这里，我们确定去泛素酶USP15是CARD9的一个新的调节因子，表明USP15与CARD9结构性结合，并去除TRIM62沉积的泛素标记。此外，USP15基因敲除和敲除特异性地增强了小鼠和人类免疫细胞中依赖CARD9的CLR信号。总之，我们的研究确定了一种新的先天性免疫信号调节因子，并为识别可能控制这些过程的其他去泛素酶提供了蓝图。
Post-translational modifications are efficient means to rapidly regulate protein function in response to a stimulus. Although ubiquitination events and the E3 ubiquitin ligases involved are increasingly characterized in many signaling pathways, their regulation by deubiquitinating enzymes remains less understood. The C-type lectin receptor (CLR) signaling adaptor CARD9 was previously reported to be activated via TRIM62-mediated ubiquitination. Here, we identify the deubiquitinase USP15 as a novel regulator of CARD9, demonstrating that USP15 constitutively associates with CARD9 and removes TRIM62-deposited ubiquitin marks. Furthermore, USP15 knockdown and knockout specifically enhance CARD9-dependent CLR signaling in both mouse and human immune cells. Altogether, our study identifies a novel regulator of innate immune signaling and provides a blueprint for the identification of additional deubiquitinases that are likely to control these processes.