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神经元中依赖胰岛素前体的 ENPL-1 和 ASNA-1 相互作用是秀丽隐杆线虫维持胰岛素分泌所必需的。

A proinsulin-dependent interaction between ENPL-1 and ASNA-1 in neurons is required to maintain insulin secretion in C. elegans.

机构信息

Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, SE413 45 Gothenburg, Sweden.

Department of Surgery, Sahlgrenska University Hospital, SE413 45 Gothenburg, Sweden.

出版信息

Development. 2023 Mar 15;150(6). doi: 10.1242/dev.201035. Epub 2023 Mar 20.

DOI:10.1242/dev.201035
PMID:36939052
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10112894/
Abstract

Neuropeptides, including insulin, are important regulators of physiological functions of the organisms. Trafficking through the Golgi is crucial for the regulation of secretion of insulin-like peptides. ASNA-1 (TRC40) and ENPL-1 (GRP94) are conserved insulin secretion regulators in Caenorhabditis elegans (and mammals), and mouse Grp94 mutants display type 2 diabetes. ENPL-1/GRP94 binds proinsulin and regulates proinsulin levels in C. elegans and mammalian cells. Here, we have found that ASNA-1 and ENPL-1 cooperate to regulate insulin secretion in worms via a physical interaction that is independent of the insulin-binding site of ENPL-1. The interaction occurs in DAF-28/insulin-expressing neurons and is sensitive to changes in DAF-28 pro-peptide levels. Consistently, ASNA-1 acted in neurons to promote DAF-28/insulin secretion. The chaperone form of ASNA-1 was likely the interaction partner of ENPL-1. Loss of asna-1 disrupted Golgi trafficking pathways. ASNA-1 localization to the Golgi was affected in enpl-1 mutants and ENPL-1 overexpression partially bypassed the ASNA-1 requirement. Taken together, we find a functional interaction between ENPL-1 and ASNA-1 that is necessary to maintain proper insulin secretion in C. elegans and provides insights into how their loss might cause diabetes in mammals.

摘要

神经肽，包括胰岛素，是生物生理功能的重要调节因子。通过高尔基体的运输对于调节胰岛素样肽的分泌至关重要。ASNA-1（TRC40）和 ENPL-1（GRP94）是秀丽隐杆线虫（和哺乳动物）中保守的胰岛素分泌调节剂，而小鼠 Grp94 突变体表现出 2 型糖尿病。ENPL-1/GRP94 结合胰岛素原并调节秀丽隐杆线虫和哺乳动物细胞中的胰岛素原水平。在这里，我们发现 ASNA-1 和 ENPL-1 通过一种不依赖于 ENPL-1 的胰岛素结合位点的物理相互作用合作调节线虫中的胰岛素分泌。这种相互作用发生在 DAF-28/胰岛素表达神经元中，并且对 DAF-28 前肽水平的变化敏感。一致地，ASNA-1 在神经元中发挥作用以促进 DAF-28/胰岛素分泌。ASNA-1 的伴侣形式可能是 ENPL-1 的相互作用伙伴。asna-1 的缺失破坏了高尔基体运输途径。ENPL-1 突变体中 ASNA-1 的定位受到影响，ENPL-1 过表达部分绕过了 ASNA-1 的需求。总之，我们发现 ENPL-1 和 ASNA-1 之间存在功能相互作用，这对于维持秀丽隐杆线虫中适当的胰岛素分泌是必要的，并为它们的缺失如何导致哺乳动物糖尿病提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/2f0120e62722/develop-150-201035-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/76e0524601b5/develop-150-201035-g1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/3c1671573eea/develop-150-201035-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/d788e8bb9ae2/develop-150-201035-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/2f0120e62722/develop-150-201035-g8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/76e0524601b5/develop-150-201035-g1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/56af08bf8f66/develop-150-201035-g2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/84f2a09045e1/develop-150-201035-g4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/3e114ca200d6/develop-150-201035-g5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/3c1671573eea/develop-150-201035-g6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/d788e8bb9ae2/develop-150-201035-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2850/10112894/2f0120e62722/develop-150-201035-g8.jpg

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