title: Absence of ataxin-3 leads to enhanced stress response in C. elegans.
abstract: Ataxin-3, the protein involved in Machado-Joseph disease, is able to bind ubiquitylated substrates and act as a deubiquitylating enzyme in vitro, and it has been involved in the modulation of protein degradation by the ubiquitin-proteasome pathway. C. elegans and mouse ataxin-3 knockout models are viable and without any obvious phenotype in a basal condition however their phenotype in stress situations has never been described.Considering the role of ataxin-3 in the protein degradation pathway, we analyzed the effects of heat shock, a known protein homeostasis stressor, in C. elegans ataxin-3 (ATX-3) knockout animals. We found that ATX-3 mutants have an exacerbated stress response and survive significantly better than wild type animals when subjected to a noxious heat shock stimulus. This increased thermotolerance of mutants was further enhanced by pre-exposure to a mild heat shock. At a molecular level, ATX-3 mutants have a distinct transcriptomic and proteomic profile with several molecular chaperones abnormally up-regulated during heat shock and recovery, consistent with the observed resistance phenotype.The improved thermotolerance in ATX-3 mutants is independent of heat shock factor 1, the maestro of the heat shock response, but fully dependent on DAF-16, a critical stress responsive transcription factor involved in longevity and stress resistance. We also show that the increased thermotolerance of ATX-3 mutants is mainly due to HSP-16.2, C12C8.1 and F44E5.5 given that the knockdown of these heat shock proteins using RNA interference causes the phenotype to revert. This report suggests that the absence of ATX-3 activates the DAF-16 pathway leading to an overexpression of molecular chaperones, which yields knockout animals with an improved capacity for dealing with deleterious stimuli.
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors.forename: Ana João
authors.initials: AJ
authors.lastname: Rodrigues
authors.forename: Andreia
authors.initials: A
authors.lastname: Neves-Carvalho
authors.forename: Andreia
authors.initials: A
authors.lastname: Teixeira-Castro
authors.forename: Anne
authors.initials: A
authors.lastname: Rokka
authors.forename: Garry
authors.initials: G
authors.lastname: Corthals
authors.forename: Elsa
authors.initials: E
authors.lastname: Logarinho
authors.forename: Patrícia
authors.initials: P
authors.lastname: Maciel
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D003080:Cold Temperature; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D018869:Heat-Shock Response / Q000235:genetics; D008136:Longevity; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C474710:heat shock factor-1, C elegans; D000067699:Ataxin-3; C519526:atx-3 protein, C elegans