Rag GTPases 介导 TFEB 和 MITF 依赖氨基酸的溶酶体募集。
Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes.
机构信息
Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
J Cell Biol. 2013 Feb 18;200(4):475-91. doi: 10.1083/jcb.201209135. Epub 2013 Feb 11.
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.
mTORC1 复合物响应能量水平、生长因子和营养物质支持细胞生长和增殖。Rag 鸟嘌呤核苷酸三磷酸酶 (GTPases) 通过促进其重新分布到溶酶体中来响应氨基酸激活 mTORC1。在本文中，我们发现了 Rag 在控制转录因子 EB（TFEB）激活中的新作用，TFEB 是自噬和溶酶体基因表达的主要调节剂。TFEB 与活性 Rag 异二聚体的相互作用促进了 TFEB 向溶酶体的募集，导致 mTORC1 依赖性磷酸化和 TFEB 抑制。TFEB 与 Rag 的相互作用需要 TFEB 的前 30 个残基和 Rag G 结构域的开关区。Rag 的消耗或失活阻止了 TFEB 向溶酶体的募集，而活性 Rag 的表达诱导了 TFEB 与溶酶体膜的关联。最后，Rag GTPases 结合并调节小眼畸形相关转录因子的激活，表明 Rag 在控制基因表达方面具有更广泛的作用。我们的工作为连接营养物质可用性和 TFEB 定位和激活的分子机制提供了新的见解。
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