Developmental and conditional regulation of DAF-2/INSR ubiquitination inCaenorhabditis elegans

Abstract

Insulin/IGF signaling (IIS) regulates developmental and metabolic plasticity. Conditional regulation of insulin-like peptide expression and secretion promotes different phenotypes in different environments. However, IIS can also be regulated by other, less-understood mechanisms. For example, stability of the only known insulin/IGF receptor inC. elegans, DAF-2/INSR, is regulated by CHIP-dependent ubiquitination. Disruption ofchn-1/CHIPreduces longevity inC. elegansby increasing DAF-2/INSR abundance and IIS activity in adults. Likewise, mutation of a ubiquitination site causesdaf-2(gk390525)to display gain-of-function phenotypes in adults. However, we show that this allele displays loss-of-function phenotypes in larvae, and that its effect on IIS activity transitions from negative to positive during development. In contrast, the allele acts like a gain-of-function in larvae cultured at high temperature, inhibiting temperature-dependent dauer formation. Disruption ofchn-1/CHIPcauses an increase in IIS activity in starved L1 larvae, unlikedaf-2(gk390525). CHN-1/CHIP ubiquitinates DAF-2/INSR at multiple sites. These results suggest that the sites that are functionally relevant to negative regulation of IIS vary in larvae and adults, at different temperatures, and in nutrient-dependent fashion, revealing additional layers of IIS regulation.