Breakdown of oxidized proteins as a part of secondary antioxidant defenses in mammalian cells

Abstract

The degradation of oxidized proteins is an essential part of antioxidant defenses against free radical attack. Selective degradation of oxidatively damaged proteins allows proteolytic systems to function directly in the removal of useless cellular debris and therefore prevent the accumulation of potentially toxic fragments or large aggregates of cross-linked proteins. The degradation of oxidized proteins in dividing mammalian cells after hydrogen peroxide treatment has been demonstrated. Cells are able to increase proteolysis rates after treatment with moderate levels of oxidants. The role of proteasome in the removal of oxidized proteins has been demonstrated by treatment of cells with an anti-sense oligodesoxynucleotide to the proteasome C2 subunit gene. This treatment decreases the proteasome content of the cells and prevents increased proteolysis rates after hydrogen peroxide treatment. Thus proteasome clearly plays a role in the removal of oxidized proteins. As part of antioxidant defenses the proteasome provides a second line of defense against the numerous radicals and oxidants which contact cells during their lifetime. The degradation of oxidatively damaged proteins enables-cells to recover from a moderate oxidant attack.

Formation of high molecular weight complexes of mutant Cu,Zn-superoxide dismutase in a mouse model for familial amyotrophic lateral sclerosis

“…Oxidative free radicals and reactive oxygen species can damage proteins by modification of amino acid side chains, fragmentation of polypeptide chains, and induction of both covalent and noncovalent aggregation; all of these adducts are substrates for proteasome-mediated degradation (40). The production of an abundant misfolded protein like SOD, compounded by the generation of oxidatively damaged proteins imposes an increased burden on the ubiquitin-proteasome pathway.…”

Differential Regulation of Plastidial and Cytosolic Isoforms of Peptide Methionine Sulfoxide Reductase in Arabidopsis

“…It is believed that the principal defense mechanism of plants and animals involves scavenging of ROS by antioxidants or via enzymes such as catalase or glutathione reductase (Davies, 1995). Oxidative damage to proteins has previously been regarded as largely irrepairable, resulting in their turnover by proteolysis (Mehta et al, 1992;Davies, 1995;Grune and Davies, 1997;Grune et al, 1997;Pell et al, 1997). However, the presence of two light-inducible p-pmsr genes in Arabidopsis strongly indicates that PMSR performs an important repair function for chloroplast proteins that are oxidized during normal photosynthesis.…”

“…Oxidation of Met residues has been implicated in several serious conditions in humans, including adult respiratory distress syndrome, rheumatoid arthritis, smokers' emphysema, and Alzheimer's disease (Abrams et al, 1981;Vogt, 1995;Moskovitz et al, 1996a;Gabitta et al, 1999). The best-characterized response to the oxidation of peptide residues in both plants and animals is the induction of proteases that cause the complete breakdown of the oxidized protein and its eventual replacement by a protein synthesized de novo (Davies, 1995;Grune and Davies, 1997;Grune et al, 1997).…”

Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

“…The 26 S proteasome is responsible for the degradation of the majority of cellular proteins through an ATP-dependent and ubiquitinmediated pathway (4 -6). In contrast, the 20 S proteasome core selectively degrades a range of different oxidized proteins in an ATP-independent manner and has been suggested to represent the primary mechanism in the rapid removal of oxidized proteins after oxidative stress (7)(8)(9)(10)(11). The signal for recognition and degradation of oxidized proteins by the 20 S proteasome is unknown but has been suggested to involve (i) exposure of hydrophobic surfaces after oxidative modification, (ii) recognition of molecular "markers" associated with the oxidative modification of specific amino acid side chains, and (iii) increases in the conformational flexibility of oxidized proteins (12)(13)(14)(15)(16).…”