IF 45.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Cell Pub Date : 2025-03-17 DOI:10.1016/j.cell.2025.02.014
Yong Jiang, Anran Dai, Yuwei Huang, Hua Li, Jian Cui, Haochen Yang, Lu Si, Tao Jiao, Zhengxu Ren, Ziwei Zhang, Si Mou, Hengrui Zhu, Wenhui Guo, Qiang Huang, Yilin Li, Manman Xue, Jingwei Jiang, Fei Wang, Li Li, Qinying Zhong, Haopeng Wang
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引用次数: 0

摘要

淋巴细胞活化基因 3(LAG3)已成为一种很有前景的癌症免疫疗法靶点,但配体接合时激活 LAG3 的机制仍不清楚。本文发现,LAG3在配体接合时会发生强有力的非K48连接的多泛素化,这促进了LAG3的抑制功能,而不是导致降解。这种泛素化可由主要组织相容性复合体II类(MHC II类)和膜结合型(而非可溶性)纤维蛋白原样蛋白1(FGL1)的参与触发。由E3连接酶c-Cbl和Cbl-b冗余介导的LAG3泛素化破坏了富含基本残基的并膜序列的膜结合,从而使LAG3胞质尾部稳定在与膜分离的构象中,使信号转导成为可能。此外,LAG3 泛素化对 LAG3 介导的体内抗肿瘤免疫抑制作用至关重要。LAG3治疗性抗体抑制LAG3泛素化,这与其检查点阻断效果相关。此外,患者队列分析表明,LAG3/CBL共表达可作为LAG3阻断反应的生物标志物。总之,我们的研究揭示了一种免疫检查点触发机制,具有转化为癌症免疫疗法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs

Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs
Lymphocyte activation gene 3 (LAG3) has emerged as a promising cancer immunotherapy target, but the mechanism underlying LAG3 activation upon ligand engagement remains elusive. Here, LAG3 was found to undergo robust non-K48-linked polyubiquitination upon ligand engagement, which promotes LAG3’s inhibitory function instead of causing degradation. This ubiquitination could be triggered by the engagement of major histocompatibility complex class II (MHC class II) and membrane-bound (but not soluble) fibrinogen-like protein 1 (FGL1). LAG3 ubiquitination, mediated redundantly by the E3 ligases c-Cbl and Cbl-b, disrupted the membrane binding of the juxtamembrane basic residue-rich sequence, thereby stabilizing the LAG3 cytoplasmic tail in a membrane-dissociated conformation enabling signaling. Furthermore, LAG3 ubiquitination is crucial for the LAG3-mediated suppression of antitumor immunity in vivo. Consistently, LAG3 therapeutic antibodies repress LAG3 ubiquitination, correlating with their checkpoint blockade effects. Moreover, patient cohort analyses suggest that LAG3/CBL coexpression could serve as a biomarker for response to LAG3 blockade. Collectively, our study reveals an immune-checkpoint-triggering mechanism with translational potential in cancer immunotherapy.
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来源期刊
Cell
Cell 生物-生化与分子生物学
CiteScore
110.00
自引率
0.80%
发文量
396
审稿时长
2 months
期刊介绍: Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.
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