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ARFRP1 依赖性高尔基支架蛋白 GOPC 是胰腺 β 细胞胰岛素分泌所必需的。

The ARFRP1-dependent Golgi scaffolding protein GOPC is required for insulin secretion from pancreatic β-cells.

机构信息

German Institute of Human Nutrition (DIfE) Potsdam-Rehbruecke, Germany; German Center for Diabetes Research (DZD) Munich Neuherberg, Germany.

Max-Delbrück Center for Molecular Medicine in the Helmholtz Association Berlin, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Germany.

出版信息

Mol Metab. 2021 Mar;45:101151. doi: 10.1016/j.molmet.2020.101151. Epub 2020 Dec 23.

DOI:10.1016/j.molmet.2020.101151
PMID:33359402
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7811047/
Abstract

OBJECTIVE

Hormone secretion from metabolically active tissues, such as pancreatic islets, is governed by specific and highly regulated signaling pathways. Defects in insulin secretion are among the major causes of diabetes. The molecular mechanisms underlying regulated insulin secretion are, however, not yet completely understood. In this work, we studied the role of the GTPase ARFRP1 on insulin secretion from pancreatic β-cells.

METHODS

A β-cell-specific Arfrp1 knockout mouse was phenotypically characterized. Pulldown experiments and mass spectrometry analysis were employed to screen for new ARFRP1-interacting proteins. Co-immunoprecipitation assays as well as super-resolution microscopy were applied for validation.

RESULTS

The GTPase ARFRP1 interacts with the Golgi-associated PDZ and coiled-coil motif-containing protein (GOPC). Both proteins are co-localized at the trans-Golgi network and regulate the first and second phase of insulin secretion by controlling the plasma membrane localization of the SNARE protein SNAP25. Downregulation of both GOPC and ARFRP1 in Min6 cells interferes with the plasma membrane localization of SNAP25 and enhances its degradation, thereby impairing glucose-stimulated insulin release from β-cells. In turn, overexpression of SNAP25 as well as GOPC restores insulin secretion in islets from β-cell-specific Arfrp1 knockout mice.

CONCLUSION

Our results identify a hitherto unrecognized pathway required for insulin secretion at the level of trans-Golgi sorting.

摘要

目的

代谢活跃组织(如胰岛)的激素分泌受特定且高度调控的信号通路控制。胰岛素分泌缺陷是糖尿病的主要原因之一。然而,调节胰岛素分泌的分子机制尚不完全清楚。在这项工作中,我们研究了 GTPase ARFRP1 在胰腺β细胞胰岛素分泌中的作用。

方法

对β细胞特异性的 Arfrp1 敲除小鼠进行表型特征分析。采用下拉实验和质谱分析筛选新的 ARFRP1 相互作用蛋白。应用共免疫沉淀实验和超分辨率显微镜进行验证。

结果

GTPase ARFRP1 与高尔基相关 PDZ 和卷曲螺旋结构域蛋白(GOPC)相互作用。这两种蛋白都在反式高尔基网络中共定位,并通过控制 SNARE 蛋白 SNAP25 的质膜定位来调节胰岛素分泌的第一和第二阶段。Min6 细胞中 GOPC 和 ARFRP1 的下调干扰了 SNAP25 的质膜定位并促进其降解,从而损害β细胞的葡萄糖刺激的胰岛素释放。反过来,SNAP25 以及 GOPC 的过表达可恢复β细胞特异性 Arfrp1 敲除小鼠胰岛中的胰岛素分泌。

结论

我们的结果确定了在反式高尔基体分拣水平上胰岛素分泌所必需的一个以前未被识别的途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/fa836dee8896/figs8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/ba6f719ef080/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/e0996c8978a8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/a75589cfc186/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/7a7b4bd6e5ee/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/b56951bc1358/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/e42389b3c367/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/0cd340c94568/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/5f6cf0b8ff13/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/052d49eb566a/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/d6eb57ad296a/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/82a051b33bf2/figs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/f2b865fdccdd/figs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/fa836dee8896/figs8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/ba6f719ef080/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/e0996c8978a8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/a75589cfc186/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/7a7b4bd6e5ee/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/b56951bc1358/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/e42389b3c367/figs1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/0cd340c94568/figs2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/5f6cf0b8ff13/figs3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/052d49eb566a/figs4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/d6eb57ad296a/figs5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/82a051b33bf2/figs6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/f2b865fdccdd/figs7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64d3/7811047/fa836dee8896/figs8.jpg

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