Ramirez Reyes Josué M J, Cuesta Rafael, Pause Arnim
Goodman Cancer Research Center, McGill University, Montréal, QC, Canada.
Department of Biochemistry, McGill University, Montréal, QC, Canada.
Front Cell Dev Biol. 2021 Apr 26;9:667311. doi: 10.3389/fcell.2021.667311. eCollection 2021.
is a tumor suppressor gene responsible for the inherited Birt-Hogg-Dubé (BHD) syndrome, which affects kidneys, skin and lungs. FLCN is a highly conserved protein that forms a complex with folliculin interacting proteins 1 and 2 (FNIP1/2). Although its sequence does not show homology to known functional domains, structural studies have determined a role of FLCN as a GTPase activating protein (GAP) for small GTPases such as Rag GTPases. FLCN GAP activity on the Rags is required for the recruitment of mTORC1 and the transcriptional factors TFEB and TFE3 on the lysosome, where mTORC1 phosphorylates and inactivates these factors. TFEB/TFE3 are master regulators of lysosomal biogenesis and function, and autophagy. By this mechanism, FLCN/FNIP complex participates in the control of metabolic processes. AMPK, a key regulator of catabolism, interacts with FLCN/FNIP complex. FLCN loss results in constitutive activation of AMPK, which suggests an additional mechanism by which FLCN/FNIP may control metabolism. AMPK regulates the expression and activity of the transcriptional cofactors PGC1α/β, implicated in the control of mitochondrial biogenesis and oxidative metabolism. In this review, we summarize our current knowledge of the interplay between mTORC1, FLCN/FNIP, and AMPK and their implications in the control of cellular homeostasis through the transcriptional activity of TFEB/TFE3 and PGC1α/β. Other pathways and cellular processes regulated by FLCN will be briefly discussed.
是一种肿瘤抑制基因，与遗传性Birt-Hogg-Dubé（BHD）综合征相关，该综合征会影响肾脏、皮肤和肺部。FLCN是一种高度保守的蛋白质，它与卵泡抑素相互作用蛋白1和2（FNIP1/2）形成复合物。尽管其序列与已知功能域没有同源性，但结构研究已确定FLCN作为小GTP酶（如Rag GTP酶）的GTP酶激活蛋白（GAP）发挥作用。FLCN对Rags的GAP活性是mTORC1以及转录因子TFEB和TFE3募集到溶酶体所必需的，在溶酶体中mTORC1会磷酸化并使这些因子失活。TFEB/TFE3是溶酶体生物发生、功能及自噬的主要调节因子。通过这种机制，FLCN/FNIP复合物参与代谢过程的调控。AMPK是分解代谢的关键调节因子，它与FLCN/FNIP复合物相互作用。FLCN缺失会导致AMPK的组成性激活，这提示了FLCN/FNIP控制代谢的另一种机制。AMPK调节转录辅因子PGC1α/β的表达和活性，PGC1α/β与线粒体生物发生和氧化代谢的调控有关。在本综述中，我们总结了目前关于mTORC1、FLCN/FNIP和AMPK之间相互作用的知识，以及它们通过TFEB/TFE3和PGC1α/β的转录活性对细胞稳态调控的影响。还将简要讨论受FLCN调节的其他途径和细胞过程。
