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Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation

Nature Chemical Biology volume 9, pages 112–118 (2013)Cite this article

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Abstract

We sought new strategies to reduce amounts of the polyglutamine androgen receptor (polyQ AR) and achieve benefits in models of spinobulbar muscular atrophy, a protein aggregation neurodegenerative disorder. Proteostasis of the polyQ AR is controlled by the heat shock protein 90 (Hsp90)- and Hsp70-based chaperone machinery, but mechanisms regulating the protein's turnover are incompletely understood. We demonstrate that overexpression of Hsp70 interacting protein (Hip), a co-chaperone that enhances binding of Hsp70 to its substrates, promotes client protein ubiquitination and polyQ AR clearance. Furthermore, we identify a small molecule that acts similarly to Hip by allosterically promoting Hsp70 binding to unfolded substrates. Like Hip, this synthetic co-chaperone enhances client protein ubiquitination and polyQ AR degradation. Both genetic and pharmacologic approaches targeting Hsp70 alleviate toxicity in a Drosophila model of spinobulbar muscular atrophy. These findings highlight the therapeutic potential of allosteric regulators of Hsp70 and provide new insights into the role of the chaperone machinery in protein quality control.

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Figure 1: Hip increases client protein ubiquitination and promotes AR112Q clearance.
Figure 2: YM-1 increases Hsp70 binding to a denatured substrate and competes with Hip for binding.
Figure 3: YM-1 increases client protein ubiquitination and diminishes AR112Q aggregation.
Figure 4: YM-1 increases Hsp70-dependent degradation of AR112Q.
Figure 5: Hsp70 allosteric activators rescue toxicity in Drosophila expressing AR52Q.
Figure 6: Model of the Hsp90- and Hsp70-based chaperone machinery and regulation of polyQ AR degradation.

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Acknowledgements

We thank S. Reddy, J. Diep and T. Washington for technical assistance and K. Takeyama (University of Tokyo) and the Bloomington Stock Center for fly strains. This work was initiated under a grant from the McKnight Foundation (to A.P.L.) and was supported by the US National Institutes of Health (NS055746, NS055746-04S1 to A.P.L.; NS059690 to J.E.G.; GM077430 to Y.O.; NS069844 to C.A.C.; NS32214 to D.E.M.; NS076189 to J.P.C.), the Muscular Dystrophy Association (MDA238924 to A.P.L.) and the US National Science Foundation (IOS-0842701 to C.A.C.).

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Authors and Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Adrienne M Wang, Yoshinari Miyata, Jason P Chua, Tomoko Komiyama, Xiaokai Li, Jason E Gestwicki & Andrew P Lieberman

  2. Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA

    Adrienne M Wang, Jason P Chua & Andrew P Lieberman

  3. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA

    Yoshinari Miyata, Tomoko Komiyama, Xiaokai Li & Jason E Gestwicki

  4. Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA

    Susan Klinedinst & Catherine A Collins

  5. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA

    Hwei-Ming Peng, Yoshihiro Morishima, William B Pratt & Yoichi Osawa

  6. Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, USA

    Jason P Chua

  7. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    Diane E Merry

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Contributions

A.M.W., S.K., Y. Miyata, H.-M.P., J.P.C., W.B.P., Y.O., C.A.C., J.E.G. and A.P.L. designed the experiments. A.M.W., S.K., Y. Miyata, H.-M.P., J.P.C., T.K., X.L. and Y. Morishima performed the experiments. A.M.W., S.K., Y. Miyata, H.-M.P., J.P.C., T.K., W.B.P., Y.O., C.A.C., J.E.G. and A.P.L. interpreted the data. Y.O., J.E.G. and D.E.M. contributed reagents or analytical tools. A.M.W., W.B.P., J.E.G. and A.P.L. wrote the paper.

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Correspondence to Jason E Gestwicki or Andrew P Lieberman.

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Wang, A., Miyata, Y., Klinedinst, S. et al. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 9, 112–118 (2013). https://doi.org/10.1038/nchembio.1140

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