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TBC1D1 相互作用蛋白 VPS13A 和 VPS13C 调节 C2C12 肌管中 GLUT4 的稳态。

TBC1D1 interacting proteins, VPS13A and VPS13C, regulate GLUT4 homeostasis in C2C12 myotubes.

机构信息

School of Biochemistry, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, BS8 1TD, UK.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Düsseldorf, Germany.

出版信息

Sci Rep. 2020 Oct 21;10(1):17953. doi: 10.1038/s41598-020-74661-1.

DOI:10.1038/s41598-020-74661-1
PMID:33087848
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7578007/
Abstract

Proteins involved in the spaciotemporal regulation of GLUT4 trafficking represent potential therapeutic targets for the treatment of insulin resistance and type 2 diabetes. A key regulator of insulin- and exercise-stimulated glucose uptake and GLUT4 trafficking is TBC1D1. This study aimed to identify proteins that regulate GLUT4 trafficking and homeostasis via TBC1D1. Using an unbiased quantitative proteomics approach, we identified proteins that interact with TBC1D1 in C2C12 myotubes including VPS13A and VPS13C, the Rab binding proteins EHBP1L1 and MICAL1, and the calcium pump SERCA1. These proteins associate with TBC1D1 via its phosphotyrosine binding (PTB) domains and their interactions with TBC1D1 were unaffected by AMPK activation, distinguishing them from the AMPK regulated interaction between TBC1D1 and AMPKα1 complexes. Depletion of VPS13A or VPS13C caused a post-transcriptional increase in cellular GLUT4 protein and enhanced cell surface GLUT4 levels in response to AMPK activation. The phenomenon was specific to GLUT4 because other recycling proteins were unaffected. Our results provide further support for a role of the TBC1D1 PTB domains as a scaffold for a range of Rab regulators, and also the VPS13 family of proteins which have been previously linked to fasting glycaemic traits and insulin resistance in genome wide association studies.

摘要

参与 GLUT4 运输时空调节的蛋白质代表了治疗胰岛素抵抗和 2 型糖尿病的潜在治疗靶点。TBC1D1 是调节胰岛素和运动刺激的葡萄糖摄取和 GLUT4 运输的关键调节剂。本研究旨在确定通过 TBC1D1 调节 GLUT4 运输和稳态的蛋白质。我们使用无偏定量蛋白质组学方法，鉴定了 C2C12 肌管中与 TBC1D1 相互作用的蛋白质，包括 VPS13A 和 VPS13C、Rab 结合蛋白 EHBP1L1 和 MICAL1 以及钙泵 SERCA1。这些蛋白质通过其磷酸酪氨酸结合（PTB）结构域与 TBC1D1 相互作用，并且它们与 TBC1D1 的相互作用不受 AMPK 激活的影响，这将它们与 TBC1D1 和 AMPKα1 复合物之间受 AMPK 调节的相互作用区分开来。VPS13A 或 VPS13C 的耗竭会导致细胞内 GLUT4 蛋白的转录后增加，并增强 AMPK 激活时细胞表面 GLUT4 水平。这种现象是特异性的 GLUT4，因为其他回收蛋白不受影响。我们的结果进一步支持 TBC1D1 PTB 结构域作为一系列 Rab 调节剂的支架的作用，以及 VPS13 家族的蛋白质，这些蛋白质以前与全基因组关联研究中的空腹血糖特征和胰岛素抵抗有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/890c7f8e598d/41598_2020_74661_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/92c8510be791/41598_2020_74661_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/173a20d3c211/41598_2020_74661_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/046ec0f0a6d2/41598_2020_74661_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/8dfc95ca7ad4/41598_2020_74661_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/890c7f8e598d/41598_2020_74661_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/92c8510be791/41598_2020_74661_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/173a20d3c211/41598_2020_74661_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/046ec0f0a6d2/41598_2020_74661_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/8dfc95ca7ad4/41598_2020_74661_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3eaa/7578007/890c7f8e598d/41598_2020_74661_Fig5_HTML.jpg

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