An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in <i>C. elegans</i>.

Abstract

In the nematode <i>C. elegans</i>, 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 <i>daf-2b</i> 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 <i>daf-2b</i> 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 <i>C. elegans</i> alternative splicing at the <i>daf-2</i> locus generates a truncated IR that fine-tunes insulin signaling in response to the environment.