Department of Bioengineering, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, China.
Department of Pharmacology and Chemical Biology, University of Pittsburgh, PA, USA.
FEBS Lett. 2021 Jan;595(1):123-132. doi: 10.1002/1873-3468.13959. Epub 2020 Nov 20.
Folliculin (FLCN) is a tumor suppressor protein involved in many cellular processes, including cell signaling, apoptosis, and autophagy. In ciliated cells, FLCN localizes to primary cilia and controls mTORC1 signaling in response to flow stress. Here, we show that the ciliary localization of FLCN requires its interaction with kinesin-2, the motor protein for anterograde intraflagellar transport. FLCN binds to kinesin-2 through a loop region in the middle of the protein. Single point mutations within this region of FLCN disrupt its kinesin-2 binding and ciliary entry. The mutants lose the ability to suppress the abnormal mTORC1/2 signaling activities and anchorage-independent growth of FLCN-deficient tumor cells. These observations suggest that ciliary localization of FLCN is essential for its function as a tumor suppressor.
卵泡抑素 (FLCN) 是一种肿瘤抑制蛋白，参与许多细胞过程，包括细胞信号转导、细胞凋亡和自噬。在纤毛细胞中，FLCN 定位于初级纤毛，并且能够响应流动应激来控制 mTORC1 信号。在这里，我们发现 FLCN 的纤毛定位需要其与驱动蛋白-2（正向纤毛内运输的运动蛋白）相互作用。FLCN 通过蛋白质中部的环区与驱动蛋白-2 结合。FLCN 中该区域的单点突变会破坏其与驱动蛋白-2 的结合和纤毛进入。突变体丧失了抑制 FLCN 缺陷型肿瘤细胞中异常的 mTORC1/2 信号活性和锚定非依赖性生长的能力。这些观察结果表明，FLCN 的纤毛定位对于其作为肿瘤抑制因子的功能至关重要。
