Proteins are major targets of oxidative modification by many environmental toxicants. They lose function &structure, and must be proteolyticaly degraded or they will aggregate and form cross- linked cellular inclusion bodies. We have shown a major role for the Proteasome in detoxifying oxidized proteins. Now we find proteasome is under dynamic control, exchanging regulators and catalytic subunits, and exhibiting de novo synthesis in adaptation to mild, acute stress. Our Long-term Goals are to understand the mechanisms by which Proteasome contributes to basal and inducible oxidative stress resistance, the contributions of this detoxification system to human health, and how aging can compromise such resistance.
Our Specific Aims are to test the following hypotheses: 1) Exposure of human HBE1 cells or primary human NHBE cells to hydrogen peroxide (H2O2), causes transient and reversible disassembly of 26S Proteasomes catalyzed by Ecm29, with stabilization of 19S regulators by HSP70. Dissociation of 26S Proteasomes prevents Nrf2 degradation, leading to Nrf2 accumulation, phosphorylation, and nuclear translocation;2) Exposure of HBE1 human cells or primary human NHBE cells to a mild adaptive dose of H2O2, causes Nrf2 to bind to ARE (or EpRE) sequences of 20S Proteasome subunit genes and Pa28??? genes, and up-regulate their expression within 5-10 hours after H2O2 exposure. The Irf-1 and/or NF?B transcription factors simultaneously bind to upstream regions of the three Immunoproteasome genes, and up-regulate Immunoproteasome and Pa28?? expression;3) Adaptation of C. elegans and D. melanogaster to H2O2 requires 20S Proteasome and Pa28? expression, via the skn-1 and cnc-C homologs of Nrf2;4)The capacity to adapt to oxidative stress declines in senescent HBE1 and primary NHBE cells, in our model of hyperoxia-accelerated aging of non-dividing HBE1 and NHBE cells, and in NHBE cells from older human donors, partly due to diminished Nrf2 and Irf-1/NF?B signaling of Proteasome, Pa2???, and Immunoproteasome synthesis. H2O2-induced expression of Pa28? and Proteasome, through Nrf2 homologs skn-1 and cnc-C, also decays during aging of C. elegans and D. melanogaster, contributing to age-related decline in overall stress resistance and adaptability.

Public Health Relevance

Oxidative damage to proteins is a well-characterized outcome of exposure to a wide variety of environmental toxicants. So serious is the problem of environmental oxidants that the NIEHS made discovering the mechanisms of oxidative stress a major focus in its 2006-2011 Strategic Plan, entitled New Frontiers in Environmental Sciences and Human Health. We seek to identify the mechanisms by which the proteasome enzyme protects against environmental oxidative stress, and allows us to adapt to increased stress levels.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES003598-25A1
Application #
8500861
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Thompson, Claudia L
Project Start
1985-06-15
Project End
2018-02-28
Budget Start
2013-07-01
Budget End
2014-02-28
Support Year
25
Fiscal Year
2013
Total Cost
$369,000
Indirect Cost
$144,000
Name
University of Southern California
Department
Type
Other Domestic Higher Education
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Pomatto, Laura C D; Raynes, Rachel; Davies, Kelvin J A (2016) The peroxisomal Lon protease LonP2 in aging and disease: functions and comparisons with mitochondrial Lon protease LonP1. Biol Rev Camb Philos Soc :
Raynes, Rachel; Juarez, Crystal; Pomatto, Laura C D et al. (2016) Aging and SKN-1-dependent Loss of 20S Proteasome Adaptation to Oxidative Stress in C. elegans. J Gerontol A Biol Sci Med Sci :
Bonet-Costa, Vicent; Pomatto, Laura Corrales-Diaz; Davies, Kelvin J A (2016) The Proteasome and Oxidative Stress in Alzheimer's Disease. Antioxid Redox Signal 25:886-901
Pomatto, Laura C D; Carney, Caroline; Shen, Brenda et al. (2016) The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress. Curr Biol :
Bota, Daniela A; Davies, Kelvin J A (2016) Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders. Free Radic Biol Med 100:188-198
Forman, Henry Jay; Bernardo, Angelito; Davies, Kelvin J A (2016) What is the concentration of hydrogen peroxide in blood and plasma? Arch Biochem Biophys 603:48-53
Davies, Kelvin J A (2016) The Oxygen Paradox, oxidative stress, and ageing. Arch Biochem Biophys 595:28-32
Davies, Kelvin J A (2016) Adaptive homeostasis. Mol Aspects Med 49:1-7
Reeg, Sandra; Jung, Tobias; Castro, José P et al. (2016) The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome. Free Radic Biol Med 99:153-166
Raynes, Rachel; Pomatto, Laura C D; Davies, Kelvin J A (2016) Degradation of oxidized proteins by the proteasome: Distinguishing between the 20S, 26S, and immunoproteasome proteolytic pathways. Mol Aspects Med 50:41-55

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