G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
G3BPs tether the TSC complex to lysosomes and suppress mTORC1 signaling.
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G3BP将TSC复合物拴系到溶酶体并抑制mTORC 1信号传导。
DOI：
10.1016/j.cell.2020.12.024
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发表时间：
2021-02-04
期刊：
影响因子：
64.5
通讯作者：
Thedieck K
中科院分区：
文献类型：
--
作者：
Prentzell MT;Rehbein U;Cadena Sandoval M;De Meulemeester AS;Baumeister R;Brohée L;Berdel B;Bockwoldt M;Carroll B;Chowdhury SR;von Deimling A;Demetriades C;Figlia G;Genomics England Research Consortium;de Araujo MEG;Heberle AM;Heiland I;Holzwarth B;Huber LA;Jaworski J;Kedra M;Kern K;Kopach A;Korolchuk VI;van 't Land-Kuper I;Macias M;Nellist M;Palm W;Pusch S;Ramos Pittol JM;Reil M;Reintjes A;Reuter F;Sampson JR;Scheldeman C;Siekierska A;Stefan E;Teleman AA;Thomas LE;Torres-Quesada O;Trump S;West HD;de Witte P;Woltering S;Yordanov TE;Zmorzynska J;Opitz CA;Thedieck K
Ras GTP酶激活蛋白结合蛋白1和2（分别为G3 BP 1和G3 BP 2）被广泛认为是应激颗粒（SG）的核心组分。我们报告说，G3 BPs驻留在溶酶体的细胞质表面。它们以非冗余的方式将结节性硬化症复合体（TSC）蛋白复合体锚至溶酶体，并抑制氨基酸和胰岛素对雷帕霉素复合体1（mTORC 1）的代谢主调节机制靶点的活化。与TSC复合物一样，G3 BP 1缺乏导致与mTORC 1活性亢进相关的表型。在肿瘤背景下，低G3 BP 1水平增强mTORC 1驱动的乳腺癌细胞运动性，并与患者的不良结局相关。此外，G3 bp 1抑制斑马鱼干扰神经元的发育和功能，导致白色物质异位和神经元过度活跃。因此，G3 BP不仅是SG的核心组分，而且是溶酶体TSC-mTORC 1信号传导的关键元件。G3 BP在TSC-mTORC 1信号传导轴中非冗余地起作用G3 BP驻留在溶酶体表面并抑制mTORC 1 TSC复合物需要G3 BP作为其溶酶体系链G3 BP 1缺乏表型模仿癌细胞和神经元中的TSC复合物损失与它们对应激颗粒的贡献不同，G3 BP通过TSC复合物的空间控制来调节mTORC 1活性。
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. G3BPs act non-redundantly in the TSC-mTORC1 signaling axis G3BPs reside at the lysosomal surface and inhibit mTORC1 The TSC complex requires G3BPs as its lysosomal tether G3BP1 deficiency phenocopies TSC complex loss in cancer cells and neurons Distinct from their contributions to stress granules, G3BPs regulate mTORC1 activity through spatial control of the TSC complex.
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影响因子：
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