Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway.
Proteasomes degrade damaged proteins formed during oxidative stress, thereby promoting cell survival. Neurodegenerative and other age-related disorders are associated with reduced proteasome activity. We show herein that expression of most subunits of 20S and 19S proteasomes, which collectively assemble the 26S proteasome, was enhanced up to threefold in livers of mice following treatment with dithiolethiones, which act as indirect antioxidants. Subunit protein levels and proteasome activity were coordinately increased. No induction was seen in mice where the transcription factor Nrf2 was disrupted. Promoter activity of the PSMB5 subunit of the 20S proteasome increased with either Nrf2 overexpression or treatment with antioxidants in mouse embryonic fibroblasts. Tandem antioxidant response elements in the proximal promoter of PSMB5 that controlled these responses were identified. We propose that induction of the 26S proteasome through the Nrf2 pathway represents an important indirect action of these antioxidants that can contribute to their protective effects against chronic diseases.
Kwak
Mi-Kyoung
MK
Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
Wakabayashi
Nobunao
N
Greenlaw
Jennifer L
JL
Yamamoto
Masayuki
M
Kensler
Thomas W
TW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D015398:Signal Transduction / Q000187:drug effects; D013871:Thiones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D009097:Multienzyme Complexes; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013871:Thiones; D013876:Thiophenes; D015534:Trans-Activators; D004247:DNA; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C478802:Psmb5 protein, mouse; C049325:1,2-dithiol-3-thione