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首页> 外文期刊>Cell discovery. >mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A
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mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A

机译：mTORC1通过控制驱动蛋白KIF13A调节6-磷酸甘露糖受体转运和T细胞对调节性T细胞的脆弱性

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Mannose-6-phosphate receptor (M6PR) that facilitates cellular uptake of M6P-bearing proteins, including serine-protease granzyme-B (Gzm-B) has an important role in T-cell activation, migration and contraction. However, molecular mechanisms controlling M6PR expression in T cells remain poorly understood. Here, we show that M6PR expression on T cells is distinctively controlled by two common γ-chain cytokines interleukin-2 (IL-2) and IL-7, and the differential M6PR expression is not caused by an altered synthesis of M6PR protein, but is a result of distinct regulation of kinesin-3 motor-protein KIF13A that transport M6PR onto cell surfaces. Using signaling pathway-specific inhibitors, we determine that IL-2 and IL-7 distinctly regulate KIF13A and β1-adaptin and cell-surface M6PR by controlling a kinase mammalian target of rapamycin complex-1 (mTORC1). Inflammatory cytokine IL-2 and prosurvival cytokine IL-7 induce strong and weak activation of mTORC1, leading to up- and downregulation of motor-protein KIF13A and KIF13A-motorized M6PR on T cells, and formation of IL-2 and IL-7 effectors with M6PRhigh and M6PRlow cell-surface expression, respectively. Inhibition of mTORC1 by rapamycin reduces T-cell expression of KIF13A and cell-surface M6PR, and increases T-cell survival in Listeria monocytogenes- infected mice. Using regulatory T (Treg)-cell-enriched mouse tumor model, we determine that M6PRhigh IL-2 effectors but not M6PRlow IL-7 effectors adoptively transferred into tumors are vulnerable to Treg Gzm-B-mediated cell apoptosis. Inhibition of mTORC1 or small interfering RNA-mediated knockdown of KIF13A or M6PR renders IL-2 effectors refractory to Treg Gzm-B lethal hit. Overall, our data offer novel mechanistic insights into T-cell M6PR regulation, and Treg-resistant/Treg-susceptible phenomenon. Furthermore, regulation of T-cell fate vis-à-vis Treg suppression via the mTORC1-KIF13A-M6PR axis provides a proof of concept for therapeutic strategies to target cancer, infectious and autoimmune diseases.
机译：6-磷酸甘露糖受体（M6PR）有助于细胞摄取含M6P的蛋白质，包括丝氨酸蛋白酶颗粒酶B（Gzm-B）在T细胞活化，迁移和收缩中起重要作用。但是，控制T细胞中M6PR表达的分子机制仍然知之甚少。在这里，我们表明，T细胞上的M6PR表达受到两种常见的γ链细胞因子白介素2（IL-2）和IL-7的独特控制，并且差异的M6PR表达不是由M6PR蛋白的合成改变引起的，而是是驱动M6PR转运至细胞表面的驱动蛋白3驱动蛋白KIF13A独特调控的结果。使用信号传导途径特异性抑制剂，我们确定IL-2和IL-7通过控制雷帕霉素复合物1（mTORC1）的激酶哺乳动物靶标，分别调节KIF13A和β1-adaptin和细胞表面M6PR。炎性细胞因子IL-2和存活细胞因子IL-7诱导mTORC1的强弱激活，导致T细胞上运动蛋白KIF13A和KIF13A驱动的M6PR上调和下调，并形成IL-2和IL-7效应子。分别具有M6PR high 和M6PR low 细胞表面表达。雷帕霉素对mTORC1的抑制作用可降低KIF13A的T细胞表达和细胞表面M6PR，并增加被单核细胞增生李斯特菌感染的小鼠的T细胞存活率。使用富含调节性T（T reg ）细胞的小鼠肿瘤模型，我们确定M6PR 高 IL-2效应子，而不是M6PR 低 IL过继转移到肿瘤中的-7种效应子易受T reg Gzm-B介导的细胞凋亡的影响。抑制mTORC1或抑制小干扰RNA介导的KIF13A或M6PR的敲低可使IL-2效应子对T Gzm-B致死性难治。总体而言，我们的数据为T细胞M6PR调控以及T reg 耐药/ T reg 易感现象提供了新颖的机理见解。此外，通过mTORC1-KIF13A-M6PR轴调控T细胞相对于Treg抑制的能力，为针对癌症，传染性和自身免疫性疾病的治疗策略提供了概念验证。

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