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UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

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Cell Stress and Chaperones Aims and scope

Abstract

As a result of exposure to stress conditions, mutations, or defects during synthesis, cellular proteins are prone to misfold. To cope with such partially denatured proteins, cells mount a regulated transcriptional response involving the Hsf1 transcription factor, which drives the synthesis of molecular chaperones and other stress-relieving proteins. Here, we show that the fission yeast Schizosaccharomyces pombe orthologues of human BAG-1, Bag101, and Bag102, are Hsp70 co-chaperones that associate with 26S proteasomes. Only a subgroup of Hsp70-type chaperones, including Ssa1, Ssa2, and Sks2, binds Bag101 and Bag102 and key residues in the Hsp70 ATPase domains, required for interaction with Bag101 and Bag102, were identified. In humans, BAG-1 overexpression is typically observed in cancers. Overexpression of bag101 and bag102 in fission yeast leads to a strong growth defect caused by triggering Hsp70 to release and activate the Hsf1 transcription factor. Accordingly, the bag101-linked growth defect is alleviated in strains containing a reduced amount of Hsf1 but aggravated in hsp70 deletion strains. In conclusion, we propose that the fission yeast UBL/BAG proteins release Hsf1 from Hsp70, leading to constitutive Hsf1 activation and growth defects.

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Acknowledgements

The authors thank Mrs. Anne-Marie Bonde-Lauridsen for expert technical assistance, Dr. Colin Gordon, Dr. Shao-Win Wang, Dr. Aleksandar Vjestica, and Dr. Snezhana Oliferenko for reagents, and Dr. Klavs B. Hendil for helpful discussions and comments on the manuscript. This work has been supported financially by grants to R.H.P. from the Lundbeck Foundation, the Danish Cancer Society, the Danish Council for Independent Research (Natural Sciences), the A.P. Møller Foundation for the Advancement of Medical Science, Aase & Ejnar Danielsens Fond, and the Novo Nordisk Foundation. This article is based upon work from COST Action (PROTEOSTASIS BM1307), supported by European Cooperation in Science and Technology (COST).

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Authors and Affiliations

  1. The Linderstrøm-Land Centre, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark

    Esben G. Poulsen, Caroline Kampmeyer, Franziska Kriegenburg, Christian Holmberg & Rasmus Hartmann-Petersen

  2. Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark

    Jens V. Johansen

  3. Institute for Genetics, University of Cologne, 50674, Cologne, Germany

    Kay Hofmann

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  1. Esben G. Poulsen
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  2. Caroline Kampmeyer
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Correspondence to Rasmus Hartmann-Petersen.

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Poulsen, E.G., Kampmeyer, C., Kriegenburg, F. et al. UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1. Cell Stress and Chaperones 22, 143–154 (2017). https://doi.org/10.1007/s12192-016-0751-z

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