Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus UAM Cantoblanco, 28079, Madrid, Spain.
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, 4072, Australia.
Sci Rep. 2017 Nov 27;7(1):16361. doi: 10.1038/s41598-017-16370-w.
Sorting nexin 27 (SNX27) recycles PSD-95, Dlg1, ZO-1 (PDZ) domain-interacting membrane proteins and is essential to sustain adequate brain functions. Here we define a fundamental SNX27 function in T lymphocytes controlling antigen-induced transcriptional activation and metabolic reprogramming. SNX27 limits the activation of diacylglycerol (DAG)-based signals through its high affinity PDZ-interacting cargo DAG kinase ζ (DGKζ). SNX27 silencing in human T cells enhanced T cell receptor (TCR)-stimulated activator protein 1 (AP-1)- and nuclear factor κB (NF-κB)-mediated transcription. Transcription did not increase upon DGKζ silencing, suggesting that DGKζ function is dependent on SNX27. The enhanced transcriptional activation in SNX27-silenced cells contrasted with defective activation of the mammalian target of rapamycin (mTOR) pathway. The analysis of Snx27 mice supported a role for SNX27 in the control of T cell growth. This study broadens our understanding of SNX27 as an integrator of lipid-based signals with the control of transcription and metabolic pathways.
分选连接蛋白 27（SNX27）可回收 PSD-95、Dlg1、ZO-1（PDZ）结构域相互作用的膜蛋白，对维持大脑功能至关重要。在这里，我们确定了 T 淋巴细胞中 SNX27 的一个基本功能，可控制抗原诱导的转录激活和代谢重编程。SNX27 通过其与 PDZ 结构域相互作用的高亲和力货物二酰基甘油（DAG）激酶 ζ（DGKζ）限制基于 DAG 的信号的激活。在人类 T 细胞中沉默 SNX27 增强了 T 细胞受体（TCR）刺激的激活蛋白 1（AP-1）和核因子 κB（NF-κB）介导的转录。DGKζ 沉默后转录没有增加，表明 DGKζ 的功能依赖于 SNX27。沉默 SNX27 的细胞中转录明显激活，而哺乳动物雷帕霉素靶蛋白（mTOR）通路的激活则受损。对 Snx27 敲除小鼠的分析支持 SNX27 在控制 T 细胞生长中的作用。这项研究拓宽了我们对 SNX27 的理解，它是一种整合了基于脂质的信号与转录和代谢途径控制的蛋白。
