Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Immunohorizons. 2020 Oct 22;4(10):670-678. doi: 10.4049/immunohorizons.2000036.
Posttranslational 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. In this study, 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.
翻译后修饰是响应刺激快速调节蛋白质功能的有效手段。尽管泛素化事件以及所涉及的E3泛素连接酶在许多信号通路中越来越多地得到表征，但去泛素化酶对它们的调控仍知之甚少。C型凝集素受体（CLR）信号衔接蛋白CARD9先前被报道通过TRIM62介导的泛素化被激活。在本研究中，我们鉴定出去泛素酶USP15是CARD9的一种新型调节因子，证明USP15与CARD9组成性结合并去除TRIM62沉积的泛素标记。此外，USP15的敲低和敲除在小鼠和人类免疫细胞中均特异性增强了CARD9依赖性的CLR信号。总之，我们的研究鉴定出一种先天性免疫信号的新型调节因子，并为鉴定可能控制这些过程的其他去泛素化酶提供了蓝图。
