title: The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis.
abstract: Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently targeted for proteasomal degradation, is determined by the interplay between ubiquitylation and deubiquitylation. A conserved factor that orchestrates distinct substrate-processing co-regulators in diverse species is the ubiquitin-selective chaperone CDC-48 (also known as p97). Several deubiquitylation enzymes (DUBs) have been shown to interact with CDC-48/p97, but the mechanistic and physiological relevance of these interactions remained elusive. Here we report a synergistic cooperation between CDC-48 and ATX-3 (the Caenorhabditis elegans orthologue of ataxin-3) in ubiquitin-mediated proteolysis and ageing regulation. Surprisingly, worms deficient for both cdc-48.1 and atx-3 demonstrated extended lifespan by up to 50%, mediated through the insulin-insulin-like growth factor 1 (IGF-1) signalling pathway. As lifespan extension specifically depends on the deubiquitylation activity of ATX-3, our findings identify a mechanistic link between protein degradation and longevity through editing of the ubiquitylation status of substrates involved in insulin-IGF-1 signalling.
authors.affiliation: Centre for Molecular Neurobiology (ZMNH), University of Hamburg, Falkenried 94, 20251 Hamburg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Kuhlbrodt
authors.forename: Philipp Christoph
authors.initials: PC
authors.lastname: Janiesch
authors.forename: Éva
authors.initials: É
authors.lastname: Kevei
authors.forename: Alexandra
authors.initials: A
authors.lastname: Segref
authors.forename: Roja
authors.initials: R
authors.lastname: Barikbin
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hoppe
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000067699:Ataxin-3; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008136:Longevity; D017827:Machado-Joseph Disease / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D007328:Insulin; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; D000067699:Ataxin-3; C519526:atx-3 protein, C elegans; D000251:Adenosine Triphosphatases; D000074405:Valosin Containing Protein