Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes.
Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes.
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DOI：
10.1083/jcb.201209135
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发表时间：
2013-02-18
期刊：
影响因子：
--
通讯作者：
Puertollano R
中科院分区：
文献类型：
--
作者：
Martina JA;Puertollano R
活性Rag GTP酶是TFEB向溶酶体募集及其被mTORC 1磷酸化所必需的，在营养丰富的条件下抑制其功能。mTORC1复合物支持细胞生长和增殖，以响应能量水平、生长因子和营养素。Rag鸟苷三磷酸酶（GTP酶）通过促进mTORC 1重新分布到溶酶体来激活mTORC 1以响应氨基酸。在本文中，我们确定了一个新的作用，Rags在控制转录因子EB（TFEB），自噬和溶酶体基因表达的主调节激活。TFEB与活性Rag异二聚体的相互作用促进TFEB向溶酶体的募集，导致mTORC 1依赖性磷酸化和TFEB的抑制。TFEB与Rags的相互作用需要TFEB的前30个残基和Rags G结构域的开关区域。Rags的耗尽或失活阻止TFEB向溶酶体的募集，而活性Rags的表达诱导TFEB与溶酶体膜的结合。最后，Rag GTPases结合并调节小眼症相关转录因子的激活，表明Rags在控制基因表达中具有更广泛的作用。我们的工作提供了新的见解的分子机制，链接营养物质的可用性和TFEB的定位和激活。
Active Rag GTPases are required for recruitment of TFEB to lysosomes and its phosphorylation by mTORC1, inhibiting its function under nutrient-rich conditions. The mTORC1 complex supports cell growth and proliferation in response to energy levels, growth factors, and nutrients. The Rag guanosine triphosphatases (GTPases) activate mTORC1 in response to amino acids by promoting its redistribution to lysosomes. In this paper, we identify a novel role for Rags in controlling activation of transcription factor EB (TFEB), a master regulator of autophagic and lysosomal gene expression. Interaction of TFEB with active Rag heterodimers promoted recruitment of TFEB to lysosomes, leading to mTORC1-dependent phosphorylation and inhibition of TFEB. The interaction of TFEB with Rags required the first 30 residues of TFEB and the switch regions of the Rags G domain. Depletion or inactivation of Rags prevented recruitment of TFEB to lysosomes, whereas expression of active Rags induced association of TFEB with lysosomal membranes. Finally, Rag GTPases bound and regulated activation of microphthalmia-associated transcription factor, suggesting a broader role for Rags in the control of gene expression. Our work provides new insight into the molecular mechanisms that link nutrient availability and TFEB localization and activation.
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影响因子：
21.3
作者：
Saucedo, LJ;Gao, XS;Edgar, BA
通讯作者：
Edgar, BA
影响因子：
4.3
作者：
Cronin JC;Wunderlich J;Loftus SK;Prickett TD;Wei X;Ridd K;Vemula S;Burrell AS;Agrawal NS;Lin JC;Banister CE;Buckhaults P;Rosenberg SA;Bastian BC;Pavan WJ;Samuels Y
通讯作者：
Samuels Y
影响因子：
11.8
作者：
Medina, Diego L.;Fraldi, Alessandro;Bouche, Valentina;Annunziata, Fabio;Mansueto, Gelsomina;Spampanato, Carmine;Puri, Claudia;Pignata, Antonella;Martina, Jose A.;Sardiello, Marco;Palmieri, Michela;Polishchuk, Roman;Puertollano, Rosa;Ballabio, Andrea
通讯作者：
Ballabio, Andrea
影响因子：
3.3
作者：
Hosokawa, Nao;Hara, Taichi;Mizushima, Noboru
通讯作者：
Mizushima, Noboru
影响因子：
64.5
作者：
Bar-Peled L;Schweitzer LD;Zoncu R;Sabatini DM
通讯作者：
Sabatini DM