Heat shock factor 1 (HSF-1) is a master transcription factor that regulates cellular responses to proteostatic stresses. In C. elegans, HSF-1 promotes long lifespan by acting as a downstream factor of insulin/IGF-1 signaling (IIS) pathway. Here we aimed at identification of novel factors that regulate lifespan acting together with HSF-1. We first carried out a genome-wide modifier RNAi screen and identified 17 RNAi clones that enhanced the sterile phenotype of reduction-of-function hsf-1(sy441) mutants. Among them we found that pfd-6/prefoldin 6 was required for the longevity of daf-2/insulin/IGF-1 receptor mutants by using RNAi and pfd-6(gk493446) mutations. We found that HSP-70, one of direct target chaperones of HSF-1, physically interacted with PFD-6, by employing a split GFP system. Therefore, HSF-1 appears to increase the levels of HSP-70 that binds PFD-6, which contributes to the longevity of daf-2 mutants. We then showed that pfd-6p::pfd-6::GFP was expressed in the hypodermis and the intestine, where tissue-specific RNAi knockdown of pfd-6 significantly suppressed the longevity of daf-2(e1370) mutants. Next, we asked how PFD-6 contributed to longevity. PFD-6 is a component of prefoldin complex as well as R2TP (Rvb1, Rvb2, Tah1/TPR-containing protein, Pih1/Protein interacting with Hsp90)/prefoldin-like complex, which have multiple functions including those as chaperones. We found that many components of R2TP/prefoldin-like complex were partially but specifically required for the longevity of daf-2 mutants, whereas the majority of prefoldin complex components were not. Thus, PFD-6 appears to act as a component of R2TP/prefoldin-like complex to mediate longevity. In conclusion, our work suggests a novel mechanism by which PFD-6, a component of R2TP/prefoldin-like complex, regulates longevity acting together with HSF-1 in IIS pathway.

Authors: Son, H.G., Seo, K., Seo, M., Baek, H., Choi, E., Park, S., Kim, E., Ahn, G.O., Hsu, A.L., Nam, H.G., Jang, S.K., Lee, S.J.V.

Affiliations:
- Center for plant Aging Research, Institute for Basic Science
- School of Interdisciplinary Bioscience and Bioengineering
- These authors contributed equally to this work
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk, 790-784, South Korea
- Department of Life Sciences
- Department of Internal Medicine, Division of Geriatric and Palliative Medicine, Ann Arbor, Michigan, United States of America
- Institute of Biochemistry and Molecular Biology, National Yang Ming University, Institute of Biochemistry and Molecular Biology, Taipei, Taiwan
- Department of New Biology, DGIST, Daegu, South Korea