Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia
Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia
复制标题
肿瘤抑制因子毛囊素通过初级纤毛调节 mTORC1
DOI：
10.1074/jbc.m116.719997
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发表时间：
2016-05-27
影响因子：
4.8
通讯作者：
Jiang, Yu
中科院分区：
文献类型：
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作者：
Zhong, Mingming;Zhao, Xuwen;Jiang, Yu
卵泡蛋白是一种与Birt-Hogg-Dube综合征(BHD)相关的肿瘤抑制因子，使患者容易发生多器官错构瘤和囊性病变。它的失活导致哺乳动物雷帕霉素复合体1靶点(MTORC1)信号通路的失控。然而，潜在的机制并没有得到很好的定义。在本研究中，我们证明了Flcn是一种纤毛蛋白，它通过初级纤毛调节mTORC1。作为对流动应激的响应，Flcn与LKB1结合，并将其募集到初级纤毛，激活位于基底体的AMPK，从而导致mTORC1下调。在缺乏FLCN的细胞中，LKB1不能在原生纤毛中积聚，基底体的AMPK保持不活跃，从而抵消了流动应激对mTORC1活性的抑制作用。我们的结果表明，Flcn是通过初级纤毛调节mTORC1的流动感觉机制的一部分。
Folliculin (FLCN) is the tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome that predisposes patients to incident of hamartomas and cysts in multiple organs. Its inactivation causes deregulation in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the underlying mechanism is poorly defined. In this study, we show that FLCN is a ciliary protein that functions through primary cilia to regulate mTORC1. In response to flow stress, FLCN associates with LKB1 and recruits the kinase to primary cilia for activation of AMPK resided at basal bodies, which causes mTORC1 down-regulation. In cells depleted of FLCN, LKB1 fails to accumulate in primary cilia and AMPK at the basal bodies remains inactive, thus nullifying the inhibitory effect of flow stress on mTORC1 activity. Our results demonstrate that FLCN is part of a flow sensory mechanism that regulates mTORC1 through primary cilia.