Premium
Signaling control of proteasome, immunoproteasome, and PA28 regulator gene expression during adaptation to oxidative stress (555.11)
Author(s) -
Davies Kelvin
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.555.11
Subject(s) - proteasome , proteolysis , microbiology and biotechnology , regulator , oxidative stress , ubiquitin , oxidative phosphorylation , cytosol , biology , chemistry , biochemistry , gene , enzyme
Levels of oxidative stress change continuously, depending on environment, metabolism, foods, drugs and medications, and radiation. Young, healthy, mammalian cells can readily adapt to increases in oxidative stress such that they become (temporarily) much more resistant to oxidative damage. Intracellular proteins are major targets of oxidative stress and it is vitally important that cells rapidly and selectively degrade mildly oxidized proteins, before they undergo more severe oxidation, aggregation, and cross‐linking. Our studies show that such adaptive responses include the immediate disassembly of the 26S proteasome (catalyzed by HSP70 and Ecm‐29) to form free 20S proteasome and 19S regulator complexes, at which point ATP/Ubiquitin‐dependent proteolysis is temporarily lost. The additional free 20S Proteasomes (+/‐ 11S or PA28 regulators) are of immediate help in degrading oxidized proteins. The original 26S Proteasomes are re‐assembled, and ATP/Ubiquitin‐dependent proteolysis is restored over a three‐hour period. During this three‐hour period, and during the subsequent 17 hours, new 20S Proteasomes, Immunoproteasomes, and 11S (PA28) proteasome regulators are synthesized, partially under the control of the Nrf2 signal transduction pathway. We have now obtained similar findings in C. elegans worms, and D. melanogaster fruit flies. Proteasome and Immunoproteasome subunit genes, and the 11S (PA28) regulator appear to be true shock/stress genes that provide significant oxidative stress protection. In older cells, Proteasome activities decline, and adaptational responses mediated by Nrf2 become sluggish or even ineffectual. The antagonistic effects of Bach1 and/or Nrf1 may actually blunt adaptive proteolytic responses to stress in older cells and organisms. Studies in animals and humans suggest that declining Proteasome activities and, perhaps, declining responsiveness to stress, may contribute to the ageing process, and to various age‐associated diseases. Grant Funding Source : NIH/NIEHS ES003598