Considering the role of ataxin-3 in protein quality control, we decided to analyze the effects of its absence in protein homeostasis stress using C. elegans ataxin-3 knockout strains. Surprisingly, the ATX-3 knockout animals displayed a significantly increased resistance to stress. This improved thermotolerance was due to a higher level of several molecular chaperones, as confirmed by transcriptomic and proteomic analysis, and was fully dependent on the transcription factor DAF-16, but less so on HSF-1. We found that HSP-16.2 was necessary for the increased thermoresistance phenotype of ATX- 3 knockout animals, while HSP-16.1 and -16.48 were not. Interestingly, as depicted in Figure 1A, ATX-3 knockout animals grown at 20uC exhibited a significant higher rate of survival compared to wild-type animals when exposed to a lethal heat shock at 35uC. Wild-type animals displayed a median life span of 9 hours, while both mutant strains had a median lifespan of 10 hours, a 10% increase in survival. As both mutants behaved Doxorubicin Topoisomerase inhibitor similarly with regards to their thermotolerance, we decided to use only thegk193 allele for further studies. As expected, daf-2 mutants, who are known to be long-lived and stress-resistant, lived significantly longer than both strains with more than 80% of animals living when no wild type or atx-3 animals remained. In addition to analyzing the animals under baseline conditions, we also grew the atx-3 mutants at a stress-threshold situation, at 25uC, and analyzed their survival when subjected to a 35uC heat shock. Regardless of the genotype, all strains displayed enhanced survival at 35uC compared to the same strains grown at 20uC. Similarly to the basal condition, atx-3 null animals survived significantly better than wild type animals, with a median survival time of 17 hours versus 13 hours respectively, representing an increase of 30% in atx-3 knockout animals . Table with lifespan results and p values in Table S1. To investigate whether the stress machinery could be activated more rapidly/efficiently in atx-3 mutants, we performed an additional experiment, in which animals were PF-4217903 pre-exposed to a non-lethal heat shock at 30uC and then transferred to the lethal temperature. This pre-exposure at 30uC is known to stimulate protective cellular mechanisms and improve the organism��s ability to cope with that and other types of stress in a process known as hormesis, which occurs in several animal species including worms. We pre-exposed the animals to the sub-lethal heat shock for 2 or 5 hours and then transferred these animals to the lethal temperature and measured their survival. After a pre-heat shock for 2 hours at 30uC, the survival curves of both wild type and atx-3 mutants shifted to the right, representing an increased survival.