德国奥尔登堡卡尔·冯·奥西茨基大学Kathrin Thedieck和德国转化癌症研究联盟（DKTK）及德国癌症研究中心（DKFZ）Christiane A. Opitz合作取得最新进展。他们发现G3BP（Ras GTPase激活蛋白结合蛋白）将TSC复合物束缚于溶酶体并抑制mTORC1信号传导。2021年1月25日出版的《细胞》杂志发表了该成果。
他们报告G3BPs驻留在溶酶体的细胞质表面。它们以非冗余方式将结节性硬化（TSC）蛋白复合物锚定在溶酶体上，并抑制氨基酸和胰岛素激活雷帕霉素复合物1（mTORC1）的代谢主调控子机制靶标。像TSC复合体一样，G3BP1缺乏引起与mTORC1过度活跃有关的表型。在肿瘤中，低G3BP1水平会增强mTORC1驱动的乳腺癌细胞运动，并与患者的不良预后相关。
此外，斑马鱼中的G3bp1抑制会干扰神经元的发育和功能，导致白质异位症和神经元过度活跃。因此，G3BPs不仅是应激颗粒（SGs）的核心组成部分，还是溶酶体TSC-mTORC1信号转导的关键因素。
研究人员表示，G3BP1和G3BP2被广泛认为是SGs的核心成分。
附：英文原文
Title: G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling
Author: Mirja Tamara Prentzell, Ulrike Rehbein, Marti Cadena Sandoval, Ann-Sofie De Meulemeester, Ralf Baumeister, Laura Brohée, Bianca Berdel, Mathias Bockwoldt, Bernadette Carroll, Suvagata Roy Chowdhury, Andreas von Deimling, Constantinos Demetriades, Gianluca Figlia, Mariana Eca Guimaraes de Araujo, Alexander M. Heberle, Ines Heiland, Birgit Holzwarth, Lukas A. Huber, Jacek Jaworski, Magdalena Kedra, Katharina Kern, Andrii Kopach, Viktor I. Korolchuk, Ineke van t Land-Kuper, Matylda Macias, Mark Nellist, Wilhelm Palm, Stefan Pusch, Jose Miguel Ramos Pittol, Michèle Reil, Anja Reintjes, Friederike Reuter, Julian R. Sampson, Chlo Scheldeman, Aleksandra Siekierska, Eduard Stefan, Aurelio A. Teleman, Laura E. Thomas, Omar Torres-Quesada, Saskia Trump, Hannah D. West, Peter de Witte, Sandra Woltering, Teodor E. Yordanov, Justyna Zmorzynska, Christiane A. Opitz, Kathrin Thedieck
Issue&Volume: 2021-01-25
Abstract: Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
DOI: 10.1016/j.cell.2020.12.024
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31694-9