title: EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan.
abstract: Epidermal growth factor (EGF) signalling regulates growth and differentiation. Here, we examine the function of EGF signalling in Caenorhabditis elegans lifespan. We find that EGF signalling regulates lifespan via the Ras-MAPK pathway and the PLZF transcription factors EOR-1 and EOR-2. As animals enter adulthood, EGF signalling upregulates the expression of genes involved in the ubiquitin proteasome system (UPS), including the Skp1-like protein SKR-5, while downregulating the expression of HSP16-type chaperones. Using reporters for global UPS activity, protein aggregation, and oxidative stress, we find that EGF signalling alters protein homoeostasis in adults by increasing UPS activity and polyubiquitination, while decreasing protein aggregation. We show that SKR-5 and the E3/E4 ligases that comprise the ubiquitin fusion degradation (UFD) complex are required for the increase in UPS activity observed in adults, and that animals that lack SKR-5 or the UFD have reduced lifespans and indications of oxidative stress. We propose that as animals enter fertile adulthood, EGF signalling switches the mechanism for maintaining protein homoeostasis from a chaperone-based approach to an approach involving protein elimination via augmented UPS activity.
authors.affiliation: Department of Genetics, The Waksman Institute, Rutgers University, Piscataway, NJ, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Jason
authors.initials: J
authors.lastname: Rogers
authors.forename: Coleen T
authors.initials: CT
authors.lastname: Murphy
authors.forename: Christopher
authors.initials: C
authors.lastname: Rongo
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051741:Kruppel-Like Transcription Factors; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D025801:Ubiquitin; D004815:Epidermal Growth Factor; D046988:Proteasome Endopeptidase Complex