Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1

Authors

  • Caroline Kumsta,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Tsui-Ting Ching,

    1. Department of Internal Medicine, Division of Geriatric and Palliative Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    Current affiliation:
    1. Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan
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  • Mayuko Nishimura,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Andrew E. Davis,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Sara Gelino,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Hannah H. Catan,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Xiaokun Yu,

    1. Department of Internal Medicine, Division of Geriatric and Palliative Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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  • Chu-Chiao Chu,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Binnan Ong,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Siler H. Panowski,

    1. The Glenn Center for Aging Research, The Salk Institute for Biological Studies, The Howard Hughes Medical Institute, La Jolla, CA, USA
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  • Nathan Baird,

    1. The Glenn Center for Aging Research, The Salk Institute for Biological Studies, The Howard Hughes Medical Institute, La Jolla, CA, USA
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  • Rolf Bodmer,

    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
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  • Ao-Lin Hsu,

    1. Department of Internal Medicine, Division of Geriatric and Palliative Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
    2. Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
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  • Malene Hansen

    Corresponding author
    1. Development, Aging and Regeneration Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
    • Correspondence

      Malene Hansen, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA-92037, USA. Tel.: +1 858-795-5223; fax: +1 858-795-5298; e-mail: mhansen@sanfordburnham.org

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Summary

Integrin-signaling complexes play important roles in cytoskeletal organization and cell adhesion in many species. Components of the integrin-signaling complex have been linked to aging in both Caenorhabditis elegans and Drosophila melanogaster, but the mechanism underlying this function is unknown. Here, we investigated the role of integrin-linked kinase (ILK), a key component of the integrin-signaling complex, in lifespan determination. We report that genetic reduction of ILK in both C. elegans and Drosophila increased resistance to heat stress, and led to lifespan extension in C. elegans without majorly affecting cytoskeletal integrity. In C. elegans, longevity and thermotolerance induced by ILK depletion was mediated by heat-shock factor-1 (HSF-1), a major transcriptional regulator of the heat-shock response (HSR). Reduction in ILK levels increased hsf-1 transcription and activation, and led to enhanced expression of a subset of genes with roles in the HSR. Moreover, induction of HSR-related genes, longevity and thermotolerance caused by ILK reduction required the thermosensory neurons AFD and interneurons AIY, which are known to play a critical role in the canonical HSR. Notably, ILK was expressed in neighboring neurons, but not in AFD or AIY, implying that ILK reduction initiates cell nonautonomous signaling through thermosensory neurons to elicit a noncanonical HSR. Our results thus identify HSF-1 as a novel effector of the organismal response to reduced ILK levels and show that ILK inhibition regulates HSF-1 in a cell nonautonomous fashion to enhance stress resistance and lifespan in C. elegans.

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