Oxidized cytoplasmic and nuclear proteins are normally degraded by the proteasome, but accumulate with age and disease. We demonstrate the importance of various forms of the proteasome during transient (reversible) adaptation (hormesis), to oxidative stress in murine embryonic fibroblasts. Adaptation was achieved by ‘pre-treatment’ with very low concentrations of H2O2, and tested by measuring inducible resistance to a subsequent much higher ‘challenge’ dose of H2O2. Following an initial direct physical activation of pre-existing proteasomes, the 20S proteasome, immunoproteasome and PA28αβ regulator all exhibited substantially increased de novo synthesis during adaptation over 24 h. Cellular capacity to degrade oxidatively damaged proteins increased with 20S proteasome, immunoproteasome and PA28αβ synthesis, and was mostly blocked by the 20S proteasome, immunoproteasome and PA28 siRNA (short interfering RNA) knockdown treatments. Additionally, PA28αβ-knockout mutants achieved only half of the H2O2-induced adaptive increase in proteolytic capacity of wild-type controls. Direct comparison of purified 20S proteasome and immunoproteasome demonstrated that the immunoproteasome can selectively degrade oxidized proteins. Cell proliferation and DNA replication both decreased, and oxidized proteins accumulated, during high H2O2 challenge, but prior H2O2 adaptation was protective. Importantly, siRNA knockdown of the 20S proteasome, immunoproteasome or PA28αβ regulator blocked 50–100% of these adaptive increases in cell division and DNA replication, and immunoproteasome knockdown largely abolished protection against protein oxidation.
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December 2010
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Research Article|
November 25 2010
The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes
Andrew M. Pickering;
Andrew M. Pickering
*Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
†Division of Molecular and Computational Biology, Department of Biological Sciences of the College of Letters, Arts and Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
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Alison L. Koop;
Alison L. Koop
*Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
†Division of Molecular and Computational Biology, Department of Biological Sciences of the College of Letters, Arts and Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
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Cheryl Y. Teoh;
Cheryl Y. Teoh
*Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
†Division of Molecular and Computational Biology, Department of Biological Sciences of the College of Letters, Arts and Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
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Gennady Ermak;
Gennady Ermak
*Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
†Division of Molecular and Computational Biology, Department of Biological Sciences of the College of Letters, Arts and Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
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Tilman Grune;
Tilman Grune
‡Institute of Nutrition, Friedrich Schiller University, Jena 07743, Germany
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Kelvin J. A. Davies
Kelvin J. A. Davies
1
*Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
†Division of Molecular and Computational Biology, Department of Biological Sciences of the College of Letters, Arts and Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, U.S.A.
1To whom correspondence should be addressed (email Kelvin@usc.edu).
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Publisher: Portland Press Ltd
Received:
June 16 2010
Revision Received:
September 24 2010
Accepted:
October 05 2010
Accepted Manuscript online:
October 05 2010
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2010 Biochemical Society
2010
Biochem J (2010) 432 (3): 585–595.
Article history
Received:
June 16 2010
Revision Received:
September 24 2010
Accepted:
October 05 2010
Accepted Manuscript online:
October 05 2010
Citation
Andrew M. Pickering, Alison L. Koop, Cheryl Y. Teoh, Gennady Ermak, Tilman Grune, Kelvin J. A. Davies; The immunoproteasome, the 20S proteasome and the PA28αβ proteasome regulator are oxidative-stress-adaptive proteolytic complexes. Biochem J 15 December 2010; 432 (3): 585–595. doi: https://doi.org/10.1042/BJ20100878
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