An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
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DOI：
10.7554/elife.49917
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发表时间：
2020-02-25
期刊：
影响因子：
7.7
通讯作者：
Gill, Matthew S.
中科院分区：
文献类型：
--
作者：
Martinez, Bryan A.;Rodrigues, Pedro Reis;Gill, Matthew S.
线虫C.在线虫中，胰岛素信号传导响应于许多胰岛素肽的分泌而调节发育和衰老。在这里，我们描述了一种新的，非信号亚型的线虫胰岛素受体（IR），ESTA-2B，调节胰岛素信号隔离的胰岛素肽。β-2B通过选择性剪接产生，并保留细胞外配体结合结构域，但缺乏细胞内信号传导结构域。一个daf-2b剪接报告揭示了这种转录本通过发展，特别是在dauer幼虫，滞育阶段与长寿的积极调节。将mScarlet敲入daf-2b基因组基因座中的CRISPR证实了DAF-2B在体内表达并且可能被分泌。遗传学研究表明，β-2B通过改变胰岛素敏感性影响dauer进入，dauer恢复和成年寿命。因此，在C. elegans在daf-2位点的选择性剪接产生了一个截短的IR，该IR响应于环境而微调胰岛素信号传导。
In the nematode C. elegans, insulin signaling regulates development and aging in response to the secretion of numerous insulin peptides. Here, we describe a novel, non-signaling isoform of the nematode insulin receptor (IR), DAF-2B, that modulates insulin signaling by sequestration of insulin peptides. DAF-2B arises via alternative splicing and retains the extracellular ligand binding domain but lacks the intracellular signaling domain. A daf-2b splicing reporter revealed active regulation of this transcript through development, particularly in the dauer larva, a diapause stage associated with longevity. CRISPR knock-in of mScarlet into the daf-2b genomic locus confirmed that DAF-2B is expressed in vivo and is likely secreted. Genetic studies indicate that DAF-2B influences dauer entry, dauer recovery and adult lifespan by altering insulin sensitivity according to the prevailing insulin milieu. Thus, in C. elegans alternative splicing at the daf-2 locus generates a truncated IR that fine-tunes insulin signaling in response to the environment.