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: Ana João Rodrigues, Andreia Neves-Carvalho, Andreia Teixeira-Castro, Anne Rokka, Garry Corthals, Elsa Logarinho, Patrícia Maciel
• Journal: PloS one (PLoS One) Vol. 6 Issue 4 Pg. e18512 (Apr 19 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21526185 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Caenorhabditis elegans Proteins
• Forkhead Transcription Factors
• Molecular Chaperones
• Nerve Tissue Proteins
• RNA, Messenger
• Transcription Factors
• daf-16 protein, C elegans
• heat shock factor-1, C elegans
• Ataxin-3
• atx-3 protein, C elegans

Topics

• Animals
• Ataxin-3
• Caenorhabditis elegans (genetics, physiology)
• Caenorhabditis elegans Proteins (metabolism)
• Cold Temperature
• Forkhead Transcription Factors
• Gene Expression Regulation
• Gene Knockout Techniques
• Heat-Shock Response (genetics)
• Longevity
• Mice
• Molecular Chaperones (genetics, metabolism)
• Mutation (genetics)
• Nerve Tissue Proteins (deficiency, metabolism)
• Proteomics
• RNA, Messenger (genetics, metabolism)
• Stress, Physiological (genetics)
• Transcription Factors (metabolism)