Department of Molecular Medicine, The Scripps Research Institute - Scripps Florida, Jupiter, United States.
Department of Neuroscience, The Scripps Research Institute - Scripps Florida, Jupiter, United States.
Elife. 2020 Feb 25;9:e49917. doi: 10.7554/eLife.49917.
In the nematode , 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 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 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 alternative splicing at the locus generates a truncated IR that fine-tunes insulin signaling in response to the environment.
在线虫中，胰岛素信号通路通过对多种胰岛素肽的分泌来调节发育和衰老。在这里，我们描述了一种线虫胰岛素受体（IR）的新型非信号同工型 DAF-2B，它通过隔离胰岛素肽来调节胰岛素信号通路。DAF-2B 通过选择性剪接产生，保留了细胞外配体结合域，但缺乏细胞内信号域。剪接报告显示，该转录本通过发育过程特别是在 dauer 幼虫期进行活跃的调控， dauer 幼虫期是一种与长寿相关的休眠阶段。通过 CRISPR 将 mScarlet 敲入基因组座证实了 DAF-2B 在体内表达，并可能被分泌。遗传研究表明，DAF-2B 通过根据流行的胰岛素环境改变胰岛素敏感性来影响 dauer 进入、 dauer 恢复和成虫寿命，从而影响 dauer 进入、 dauer 恢复和成虫寿命。因此，在该基因座的选择性剪接产生了一种截断的 IR，它可以根据环境精细调节胰岛素信号通路。
