Rehbein Ulrike, Prentzell Mirja Tamara, Cadena Sandoval Marti, Heberle Alexander Martin, Henske Elizabeth P, Opitz Christiane A, Thedieck Kathrin
Laboratory for Metabolic Signaling, Institute of Biochemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria.
Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany.
Front Cell Dev Biol. 2021 Oct 29;9:751892. doi: 10.3389/fcell.2021.751892. eCollection 2021.
The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM).
结节性硬化蛋白复合物（TSC复合物）是代谢信号和细胞应激的关键整合者。在应对营养短缺和应激时，TSC复合物在溶酶体处抑制雷帕霉素靶蛋白复合物1（mTORC1）。mTORC1也受到应激颗粒（SGs）的抑制，应激颗粒是使mTORC1解离的RNA-蛋白质聚集体。mTORC1在溶酶体和SGs处募集的机制已得到充分研究。相比之下，关于TSC复合物在溶酶体处募集的分子细节直到最近才出现。TSC复合物亚基1（TSC1）与溶酶体的磷脂酰肌醇-3,5-二磷酸[PI(3,5)P2]结合。当不存在SGs时，SG组装因子1和2（G3BP1/2）在募集TSC2方面具有意想不到的溶酶体功能。此外，高密度脂蛋白结合蛋白（HDLBP，也称为vigilin）在应激条件下将TSC2募集到SGs处。在这篇小型综述中，我们整合了TSC复合物在溶酶体和SGs处募集的分子机制。我们讨论了它们在癌症细胞增殖和迁移以及结节性硬化症复杂疾病（TSC）和淋巴管平滑肌瘤病（LAM）的临床表现背景下的相互作用。
