A20 intrinsically influences human effector T-cell survival and function by regulating both NF-κB and JNK signaling

IF 4.5 3区 医学 Q2 IMMUNOLOGY
Gina Dabbah-Krancher, Allison Ruchinskas, Melissa A. Kallarakal, Katherine P. Lee, Bradly M. Bauman, Benjamin Epstein, Hongli Yin, Daniel Krappmann, Brian C. Schaefer, Andrew L. Snow
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引用次数: 0

Abstract

A20 is a dual-function ubiquitin-editing enzyme that maintains immune homeostasis by restraining inflammation. Although A20 serves a similar negative feedback function for T-cell receptor (TCR) signaling, the molecular mechanisms utilized and their ultimate impact on human T-cell function remain unclear. TCR engagement triggers the assembly of the CARD11-BCL10-MALT1 (CBM) protein complex, a signaling platform that governs the activation of downstream transcription factors including NF-κB and c-Jun/AP-1. Utilizing WT and A20 knockout Jurkat T cells, we found that A20 is required to negatively regulate NF-κB and JNK. Utilizing a novel set of A20 mutants in NF-κB and AP-1-driven reporter systems, we discovered the ZnF7 domain is crucial for negative regulatory capacity, while deubiquitinase activity is dispensable. Successful inactivation of A20 in human primary effector T cells congruently conferred sustained NF-κB and JNK signaling, including enhanced upregulation of activation markers, and increased secretion of several cytokines including IL-9. Finally, loss of A20 in primary human T cells resulted in decreased sensitivity to restimulation-induced cell death and increased sensitivity to cytokine withdrawal-induced death. These findings demonstrate the importance of A20 in maintaining T-cell homeostasis via negative regulation of both NF-κB and JNK signaling.

Abstract Image

A20 通过调节 NF-κB 和 JNK 信号,从本质上影响人类效应 T 细胞的存活和功能。
A20 是一种具有双重功能的泛素编辑酶,它通过抑制炎症来维持免疫平衡。虽然A20对T细胞受体(TCR)信号转导也有类似的负反馈功能,但其分子机制及其对人类T细胞功能的最终影响仍不清楚。TCR接合会触发CARD11-BCL10-MALT1(CBM)蛋白复合物的组装,这是一个信号平台,可控制下游转录因子(包括NF-κB和c-Jun/AP-1)的激活。利用 WT 和 A20 基因敲除的 Jurkat T 细胞,我们发现 A20 是负向调节 NF-κB 和 JNK 所必需的。在 NF-κB 和 AP-1 驱动的报告系统中利用一组新的 A20 突变体,我们发现 ZnF7 结构域对于负调控能力至关重要,而去泛素化酶活性则是可有可无的。在人类原代效应 T 细胞中成功失活 A20 可使 NF-κB 和 JNK 信号持续传递,包括增强活化标志物的上调和增加包括 IL-9 在内的多种细胞因子的分泌。最后,原代人类 T 细胞中 A20 的缺失会降低对再刺激诱导的细胞死亡的敏感性,并增加对细胞因子撤出诱导的细胞死亡的敏感性。这些研究结果表明了 A20 通过对 NF-κB 和 JNK 信号转导的负调控在维持 T 细胞稳态方面的重要性。
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来源期刊
CiteScore
8.30
自引率
3.70%
发文量
224
审稿时长
2 months
期刊介绍: The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.
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