mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells.
mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells.
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DOI：
10.1091/mbc.e15-05-0272
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发表时间：
2016-01-15
影响因子：
3.3
通讯作者：
Botelho RJ
中科院分区：
文献类型：
--
作者：
Saric A;Hipolito VE;Kay JG;Canton J;Antonescu CN;Botelho RJ
LPS 引起巨噬细胞和树突状细胞中的溶酶体管状形成。 PI3K-Akt-mTOR 通路是 LPS 诱导的溶酶体管状形成所必需的，而 mTOR 是树突状细胞中 MHC-II 呈递所必需的。有证据表明，mTOR 可能通过 Arl8b 调节微管运动活性来控制溶酶体管化。暴露于脂多糖 (LPS) 的巨噬细胞和树突状细胞将其溶酶体从小的点状细胞器转变为小管网络。管状溶酶体与吞噬体成熟、液相保留和抗原呈递有关。人们越来越认识到溶酶体通过激酶 mTOR 作为压力和细胞代谢状态的传感器。在这里，我们表明 LPS 刺激 mTOR，并且 mTOR 是 LPS 诱导的溶酶体管状和巨噬细胞和树突细胞中主要组织相容性复合物 II 分泌所必需的。具体来说，我们表明经典的磷脂酰肌醇 3-激酶-Akt-mTOR 信号通路独立于 IRAK1/4 和 TBK 调节 LPS 诱导的溶酶体管状化。值得注意的是，我们发现 LPS 处理增强了膜相关 Arl8b 的水平，Arl8b 是一种管道形成所需的溶酶体 GTP 酶，以 mTOR 依赖性方式促进驱动蛋白依赖性溶酶体向细胞外周运动。这表明 mTOR 可能与 Arl8b-驱动蛋白机制相互作用。为了进一步支持这一观点，我们证明 mTOR 拮抗剂可以阻止用醋酸盐处理的细胞中溶酶体的向外运动，但在醋酸盐去除后对逆行运动没有影响。总的来说，我们的工作提供了诱人的证据，证明 mTOR 通过调节白细胞中基于微管的运动活动来控制溶酶体形态和运输。
LPS causes lysosome tubulation in macrophages and dendritic cells. The PI3K-Akt-mTOR pathway is necessary for LPS-induced lysosome tubulation, and mTOR is required for MHC-II presentation in dendritic cells. Evidence shows that mTOR may control lysosome tubulation by modulating microtubule motor activity through Arl8b. Macrophages and dendritic cells exposed to lipopolysaccharide (LPS) convert their lysosomes from small, punctate organelles into a network of tubules. Tubular lysosomes have been implicated in phagosome maturation, retention of fluid phase, and antigen presentation. There is a growing appreciation that lysosomes act as sensors of stress and the metabolic state of the cell through the kinase mTOR. Here we show that LPS stimulates mTOR and that mTOR is required for LPS-induced lysosome tubulation and secretion of major histocompatibility complex II in macrophages and dendritic cells. Specifically, we show that the canonical phosphatidylinositol 3-kinase–Akt–mTOR signaling pathway regulates LPS-induced lysosome tubulation independently of IRAK1/4 and TBK. Of note, we find that LPS treatment augmented the levels of membrane-associated Arl8b, a lysosomal GTPase required for tubulation that promotes kinesin-dependent lysosome movement to the cell periphery, in an mTOR-dependent manner. This suggests that mTOR may interface with the Arl8b-kinesin machinery. To further support this notion, we show that mTOR antagonists can block outward movement of lysosomes in cells treated with acetate but have no effect in retrograde movement upon acetate removal. Overall our work provides tantalizing evidence that mTOR plays a role in controlling lysosome morphology and trafficking by modulating microtubule-based motor activity in leukocytes.