Carter Nicole M, Hankore Wihib D, Yang Yong-Kang, Yang Chao, Hutcherson Shelby M, Fales Wyatt, Ghosh Anushka, Mongia Piyusha, Mackinnon Sophie, Brennan Anna, Leone Robert D, Pomerantz Joel L
Department of Biological Chemistry and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sci Immunol. 2025 Mar 14;10(105):eadn8715. doi: 10.1126/sciimmunol.adn8715.
Antigen receptor signaling pathways that control lymphocyte activation depend on signaling hubs and negative regulatory proteins to fine-tune signaling outputs to ensure host defense and avoid pathogenic responses. Caspase recruitment domain-containing protein 11 (CARD11) is a critical signaling scaffold that translates T cell receptor (TCR) triggering into the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), mechanistic target of rapamycin (mTOR), and Akt. Here, we identify glutamine-rich protein 1 (QRICH1) as a regulator of CARD11 signaling that mediates an intracellular checkpoint for CD8 T cell activation. QRICH1 associates with CARD11 after TCR engagement and negatively regulates CARD11 signaling to NF-κB. QRICH1 binding to CARD11 is controlled by an autoregulatory intramolecular interaction between QRICH1 domains of previously uncharacterized function. QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8 T cells by regulating numerous genes critical for CD8 T cell function. Our results define a component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.
控制淋巴细胞活化的抗原受体信号通路依赖于信号枢纽和负调节蛋白来微调信号输出，以确保宿主防御并避免致病性反应。含半胱天冬酶招募结构域蛋白11（CARD11）是一种关键的信号支架，可将T细胞受体（TCR）触发转化为核因子κB（NF-κB）、c-Jun氨基末端激酶（JNK）、雷帕霉素作用靶点（mTOR）和Akt的激活。在此，我们鉴定出富含谷氨酰胺蛋白1（QRICH1）是CARD11信号的调节因子，介导CD8 T细胞活化的细胞内检查点。TCR参与后，QRICH1与CARD11结合，并对CARD11向NF-κB的信号传导起负调节作用。QRICH1与CARD11的结合受功能未知的QRICH1结构域之间的自动调节分子内相互作用控制。QRICH1通过调节对CD8 T细胞功能至关重要的众多基因，控制CD8 T细胞的抗原诱导活化、增殖和效应状态。我们的结果确定了抗原受体信号通路的一个组成部分，该部分可根据抗原识别微调效应输出。
