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GATOR1 依赖性募集 FLCN-FNIP 至溶酶体，以响应氨基酸协调 Rag GTP 酶异二聚体核苷酸状态。

GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids.

机构信息

Department of Cell Biology, Yale University School of Medicine, New Haven, CT.

Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.

出版信息

J Cell Biol. 2018 Aug 6;217(8):2765-2776. doi: 10.1083/jcb.201712177. Epub 2018 May 30.

DOI:10.1083/jcb.201712177
PMID:29848618
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6080935/
Abstract

Folliculin (FLCN) is a tumor suppressor that coordinates cellular responses to changes in amino acid availability via regulation of the Rag guanosine triphosphatases. FLCN is recruited to lysosomes during amino acid starvation, where it interacts with RagA/B as a heterodimeric complex with FLCN-interacting proteins (FNIPs). The FLCN-FNIP heterodimer also has GTPase-activating protein (GAP) activity toward RagC/D. These properties raised two important questions. First, how is amino acid availability sensed to regulate lysosomal abundance of FLCN? Second, what is the relationship between FLCN lysosome localization, RagA/B interactions, and RagC/D GAP activity? In this study, we show that RagA/B nucleotide status determines the FLCN-FNIP1 recruitment to lysosomes. Starvation-induced FLCN-FNIP lysosome localization requires GAP activity toward Rags 1 (GATOR1), the GAP that converts RagA/B to the guanosine diphosphate (GDP)-bound state. This places FLCN-FNIP recruitment to lysosomes under the control of amino acid sensors that act upstream of GATOR1. By binding to RagA/B and acting on RagC/D, FLCN-FNIP can coordinate nucleotide status between Rag heterodimer subunits in response to changes in amino acid availability.

摘要

成纤维细胞生长因子受体底物 23（Fibroblast growth factor receptor substrate 23，FRS23）是一种肿瘤抑制因子，通过调节 Rag 鸟嘌呤三核苷酸酶（guanine triphosphatases，GTPases）来协调细胞对氨基酸可用性变化的反应。在氨基酸饥饿时，FRS23 被招募到溶酶体，在溶酶体中，它与 RagA/B 形成异二聚体复合物，与 FRS23 相互作用的蛋白（FLCN-interacting proteins，FNIPs）。FRS23-FNIP 异二聚体对 RagC/D 也具有 GTPase 激活蛋白（GAP）活性。这些特性提出了两个重要问题。首先，氨基酸可用性如何被感知来调节 FRS23 在溶酶体中的丰度？其次，FRS23 溶酶体定位、RagA/B 相互作用和 RagC/D GAP 活性之间的关系是什么？在这项研究中，我们表明 RagA/B 核苷酸状态决定了 FRS23-FNIP1 向溶酶体的募集。饥饿诱导的 FRS23-FNIP 溶酶体定位需要 RagA/B 的 GAP 活性（GATOR1），即 GAP 可将 RagA/B 转换为鸟苷二磷酸（guanosine diphosphate，GDP）结合状态。这使得 FRS23-FNIP 向溶酶体的募集受到位于 GATOR1 上游的氨基酸传感器的控制。通过与 RagA/B 结合并作用于 RagC/D，FRS23-FNIP 可以协调 Rag 异二聚体亚基之间的核苷酸状态，以响应氨基酸可用性的变化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/8e5ed5c7287b/JCB_201712177_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/0441dcb6aaeb/JCB_201712177_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/14f89de570c1/JCB_201712177_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/da5127919d6e/JCB_201712177_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/6a5540e16fac/JCB_201712177_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/6d891b620f20/JCB_201712177_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/39464eed06d7/JCB_201712177_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/cb8f1dee0410/JCB_201712177_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/8068725dc642/JCB_201712177_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/8e5ed5c7287b/JCB_201712177_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/0441dcb6aaeb/JCB_201712177_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/14f89de570c1/JCB_201712177_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/da5127919d6e/JCB_201712177_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/6a5540e16fac/JCB_201712177_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/6d891b620f20/JCB_201712177_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/39464eed06d7/JCB_201712177_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/cb8f1dee0410/JCB_201712177_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/8068725dc642/JCB_201712177_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc22/6080935/8e5ed5c7287b/JCB_201712177_Fig9.jpg

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