EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan.

TitleEGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan.
Publication TypeJournal Article
Year of Publication2011
AuthorsLiu G, Rogers J, Murphy CT, Rongo C
JournalEMBO J
Volume30
Issue15
Pagination2990-3003
Date Published2011 Jun 14
ISSN1460-2075
KeywordsAging, Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Epidermal Growth Factor, Kruppel-Like Transcription Factors, Molecular Chaperones, Nuclear Proteins, Proteasome Endopeptidase Complex, Signal Transduction, Ubiquitin
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.

DOI10.1038/emboj.2011.195
Alternate JournalEMBO J.
PubMed ID21673654
PubMed Central IDPMC3160178
Grant ListR01 NS42023 / NS / NINDS NIH HHS / United States
R01 NS042023 / NS / NINDS NIH HHS / United States
T32 GM 007388 / GM / NIGMS NIH HHS / United States
R01 AG034446 / AG / NIA NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States