Degradation of oxidized proteins in mammalian cells

Abstract

Protein oxidation in vivo is a natural consequence of aerobic life. Oxygen radicals and other activated oxygen species generated as by-products of cellular metabolism or from environmental sources cause modifications to the amino acids of proteins that generally result in loss of protein function/enzymatic activity. Oxidatively modified proteins can undergo direct chemical fragmentation or can form large aggregates due to covalent cross-linking reactions and increased surface hydrophobicity. Mammalian cells exhibit only limited direct repair mechanisms and most oxidized proteins undergo selective proteolysis. The proteasome appears to be largely responsible for the degradation of soluble intracellular proteins. In most cells, oxidized proteins are cleaved in an ATP-and ubiquitin-independent pathway by the 20 S "core" proteasome. The proteasome complex recognizes hydrophobic amino acid residues, aromatic residues, and bulky aliphatic residues that are exposed during the oxidative rearrangement of secondary and tertiary protein structure: increased surface hydrophobicity is a feature common to all oxidized proteins so far tested. The recognition of such (normally shielded) hydrophobic residues is the suggested mechanism by which proteasome catalyzes the selective removal of oxidatively modified cell proteins. By minimizing protein aggregation and cross-linking and by removing potentially toxic protein fragments, proteasome plays a key role in the overall antioxidant defenses that minimize the ravages of aging and disease.

The proteasome and its role in the degradation of oxidized proteins

“…Since it is assumed that various oxidants are involved in the formation of various forms of oxidized proteins, it seems to be clear that there should be a common recognition mechanism. It was proposed by the groups of Stadtman and Davies (118)(119)(120) and later confirmed by our group (121)(122)(123)(124) that this common recognition motive is the exposure of hydrophobic amino acids to the surface of the protein, which means at least a partial unfolding of the substrate. The arings of the 20S ''core'' proteasome are responsible for substrate recognition and binding.…”

Redox regulation of the proteasome in T lymphocytes during aging

“…Oxidatively modified proteins have been demonstrated to be preferentially degraded in vitro by the 20S proteasome in an ATP-independent fashion [14,15,20,39]. While earlier studies employing fibroblasts have suggested that the 20S proteasome might be resistant to ageassociated or oxidative stress-induced modifications [18,42] recent studies employing cardiac muscles and liver from aged rodent cohorts, demonstrate significant decline in 20S proteasomal activities [21,43].…”

“…Besides targeted degradation of regulatory proteins, an important function of the proteasome is the degradation of oxidized and aberrant proteins [14][15][16][17]. Increased accumulation of highly oxidized and cross-linked protein aggregates within the cell observed during aging has been attributed to decreased proteasome function [18,19].…”

Comparative transcriptome analysis of the lichen-forming fungus Endocarpon pusillum elucidates its drought adaptation mechanisms

“…In contrast, GroEL generally participates in response to the reduction in folding efficiency induced by macromolecule aggregation. The roles of proteasome are to degrade unnecessary or damaged proteins [57,58], and it has been found that genes encoding proteasomes are up-regulated under stress [59,60]. The up-regulated expression of chaperone genes demonstrates that E. pusillum can likely cope with problems associated with protein misfolding and aggregation induced by desiccation through up-regulating its main chaperones.…”