TY - JOUR TI - An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans AU - Martinez, Bryan A AU - Reis Rodrigues, Pedro AU - Nuñez Medina, Ricardo M AU - Mondal, Prosenjit AU - Harrison, Neale J AU - Lone, Museer A AU - Webster, Amanda AU - Gurkar, Aditi U AU - Grill, Brock AU - Gill, Matthew S A2 - Sengupta, Piali A2 - Banerjee, Utpal VL - 9 PY - 2020 DA - 2020/02/25 SP - e49917 C1 - eLife 2020;9:e49917 DO - 10.7554/eLife.49917 UR - https://doi.org/10.7554/eLife.49917 AB - 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. KW - dauer formation KW - alternative splicing KW - insulin sensitivity KW - DAF-2 KW - aging JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -