Preferential degradation of oxidized proteins by the 20S proteasome may be inhibited in aging and in inflammatory neuromuscular diseases.
Free radicals produced by chronic inflammation cause cumulative damage to cellular macromolecules and appear to contribute to senescence/aging, age-related disorders, and neuromuscular degenerative diseases such as inclusion-body myositis. Proteins are major targets for oxidative damage (in addition to DNA and lipids) and the accumulation of oxidized proteins has been reported in many aging and disease models. In young and healthy individuals, moderately oxidized soluble cell proteins are selectively and rapidly degraded by the 20S proteasome. The mechanism of selective proteolysis appears to depend upon oxidation-induced protein unfolding, with increasing surface hydrophobicity as (previously shielded) hydrophobic residues are exposed from the interior. The 20S proteasome can preferentially bind to and degrade such mildly oxidized, hydrophobic proteins without a need for ubiquitin targeting or ATP activation. Severely oxidized, aggregated, and crosslinked proteins, however, are poor substrates for degradation and actually inhibit the proteasome. During aging, and in many age-related diseases/disorders, the proteasome is progressively inhibited by binding to increasing levels of oxidized and cross-linked protein aggregates. Cellular aging and inflammatory neuromuscular degenerative diseases probably include both an increase in the generation of reactive oxygen species as well as a decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence.
Davies
Kelvin J A
KJ
The Ethel Percy Andrus Gerontology Center, Division of Molecular & Computational Biology, University of Southern California, Los Angeles, CA, USA. Kelvin@usc.edu
Shringarpure
Reshma
R
D000375:Aging / Q000378:metabolism*; D016922:Cellular Senescence; D006801:Humans; D018979:Myositis, Inclusion Body / Q000378:metabolism; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011489:Protein Denaturation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D061988:Proteasome Inhibitors; D011506:Proteins; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex