Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress.
The ability to adapt to acute oxidative stress (e.g. H(2)O(2), peroxynitrite, menadione, and paraquat) through transient alterations in gene expression is an important component of cellular defense mechanisms. We show that such adaptation includes Nrf2-dependent increases in cellular capacity to degrade oxidized proteins that are attributable to increased expression of the 20 S proteasome and the Pa28αβ (11 S) proteasome regulator. Increased cellular levels of Nrf2, translocation of Nrf2 from the cytoplasm to the nucleus, and increased binding of Nrf2 to antioxidant response elements (AREs) or electrophile response elements (EpREs) in the 5'-untranslated region of the proteasome β5 subunit gene (demonstrated by chromatin immunoprecipitation (or ChIP) assay) are shown to be necessary requirements for increased proteasome/Pa28αβ levels, and for maximal increases in proteolytic capacity and stress resistance; Nrf2 siRNA and the Nrf2 inhibitor retinoic acid both block these adaptive changes and the Nrf2 inducers DL-sulforaphane, lipoic acid, and curcumin all replicate them without oxidant exposure. The immunoproteasome is also induced during oxidative stress adaptation, contributing to overall capacity to degrade oxidized proteins and stress resistance. Two of the three immunoproteasome subunit genes, however, contain no ARE/EpRE elements, and Nrf2 inducers, inhibitors, and siRNA all have minimal effects on immunoproteasome expression during adaptation to oxidative stress. Thus, immunoproteasome appears to be (at most) minimally regulated by the Nrf2 signal transduction pathway.
Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, Arts & Sciences, University of Southern California, Los Angeles, California 90089; Division of Molecular and Computational Biology, Department of Biological Sciences of the Dornsife College of Letters, Arts & Sciences, University of Southern California, Los Angeles, California 90089.
Andrew M
AM
Pickering
Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, Arts & Sciences, University of Southern California, Los Angeles, California 90089; Division of Molecular and Computational Biology, Department of Biological Sciences of the Dornsife College of Letters, Arts & Sciences, University of Southern California, Los Angeles, California 90089.
Robert A
RA
Linder
Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, Arts & Sciences, University of Southern California, Los Angeles, California 90089; University of California at Merced, Merced, California 95343.
Hongqiao
H
Zhang
Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, Arts & Sciences, University of Southern California, Los Angeles, California 90089; University of California at Merced, Merced, California 95343.
Henry J
HJ
Forman
Ethel Percy Andrus Gerontology Center of the Davis School of Gerontology, Arts & Sciences, University of Southern California, Los Angeles, California 90089; Division of Molecular and Computational Biology, Department of Biological Sciences of the Dornsife College of Letters, Arts & Sciences, University of Southern California, Los Angeles, California 90089. Electronic address: kelvin@usc.edu.
Kelvin J A
KJA
Davies
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D017879:Isothiocyanates; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D013454:Sulfoxides; D008063:Thioctic Acid / Q000494:pharmacology; D013861:Thiocyanates / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D000975:Antioxidants; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013454:Sulfoxides; D013861:Thiocyanates; D014212:Tretinoin; D008063:Thioctic Acid; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse; C486214:Psme2 protein, mouse; C016766:sulforaphane; D003474:Curcumin