Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development

• Published in: The EMBO journal Vol. 32; no. 12; pp. 1745 - 1760
• Main Authors: Hung, Wesley L, Hwang, Christine, Gao, ShangBang, Liao, Edward H, Chitturi, Jyothsna, Wang, Ying, Li, Hang, Stigloher, Christian, Bessereau, Jean-Louis, Zhen, Mei
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 12.06.2013; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; fsn-1 ubiquitin ligase; HEK293 Cells; Humans; Insulin; Insulin - genetics; Insulin - metabolism; insulin/IGF signalling; Ligands; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; MAP Kinase Signaling System - physiology; Muscles - metabolism; Mutation; Neurons; Proprotein Convertase 2 - genetics; Proprotein Convertase 2 - metabolism; Signaling; Somatomedins - genetics; Somatomedins - metabolism; synapse development; Synapses - genetics; Synapses - metabolism; Ubiquitination - physiology
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2013.91

A neuronal F‐box protein FSN‐1 regulates Caenorhabditis elegans neuromuscular junction development by negatively regulating DLK‐mediated MAPK signalling. In the present study, we show that attenuation of insulin/IGF signalling also contributes to FSN‐1‐dependent synaptic development and function. The aberrant synapse morphology and synaptic transmission in fsn‐1 mutants are partially and specifically rescued by reducing insulin/IGF‐signalling activity in postsynaptic muscles, as well as by reducing the activity of EGL‐3, a prohormone convertase that processes agonistic insulin/IGF ligands INS‐4 and INS‐6, in neurons. FSN‐1 interacts with, and potentiates the ubiquitination of EGL‐3 in vitro, and reduces the EGL‐3 level in vivo. We propose that FSN‐1 may negatively regulate insulin/IGF signalling, in part, through EGL‐3‐dependent insulin‐like ligand processing. The E3 ligase FSN‐1 regulates insulin signalling and synapse development in C. elegans by targeting EGL‐3, a prohormone convertase that processes insulin ligands.