Hyperphosphorylated tau proteins accumulate in the paired helical filaments of neurofibrillary tangles seen in such tauopathies as Alzheimer's disease. In the present paper we show that tau turnover is dependent on degradation by the proteasome (inhibited by MG132) in HT22 neuronal cells. Recombinant human tau was rapidly degraded by the 20 S proteasome in vitro, but tau phosphorylation by GSK3beta (glycogen synthase kinase 3beta) significantly inhibited proteolysis. Tau phosphorylation was increased in HT22 cells by OA [okadaic acid; which inhibits PP (protein phosphatase) 1 and PP2A] or CsA [cyclosporin A; which inhibits PP2B (calcineurin)], and in PC12 cells by induction of a tet-off dependent RCAN1 transgene (which also inhibits PP2B). Inhibition of PP1/PP2A by OA was the most effective of these treatments, and tau hyperphosphorylation induced by OA almost completely blocked tau degradation in HT22 cells (and in cell lysates to which purified proteasome was added) even though proteasome activity actually increased. Many tauopathies involve both tau hyperphosphorylation and the oxidative stress of chronic inflammation. We tested the effects of both cellular oxidative stress, and direct tau oxidative modification in vitro, on tau proteolysis. In HT22 cells, oxidative stress alone caused no increase in tau phosphorylation, but did subtly change the pattern of tau phosphorylation. Tau was actually less susceptible to direct oxidative modification than most cell proteins, and oxidized tau was degraded no better than untreated tau. The combination of oxidative stress plus OA treatment caused extensive tau phosphorylation and significant inhibition of tau degradation. HT22 cells transfected with tau-CFP (cyan fluorescent protein)/tau-GFP (green fluorescent protein) constructs exhibited significant toxicity following tau hyperphosphorylation and oxidative stress, with loss of fibrillar tau structure throughout the cytoplasm. We suggest that the combination of tau phosphorylation and tau oxidation, which also occurs in tauopathies, may be directly responsible for the accumulation of tau aggregates.
The proteasome has an important role in the degradation of normal, damaged, mutant, or misfolded proteins. This includes the degradation of normal and regulatory proteins in the cellular metabolism and additionally the removal of damaged proteins as a stress response. The two well-described proteasome regulators, the 11S and the 19S regulators, forming together with the 20S 'core' proteasome various forms of the proteasome, including the ATP-stimulated 26S proteasome. As a result of aerobic metabolism, reactive oxygen species (ROS) are constantly generated during the lifetime of biological organisms. Consequently a permanent generation of oxidative damage takes place. This includes the formation of oxidatively modified proteins. These oxidized protein derivatives tend to aggregate, and accumulation of these aggregates may lead to cell death. To prevent this, such oxidatively modified proteins are selectively recognized and either repaired or degraded by the proteasome. The current knowledge of the repair systems and the degradation mechanism is reviewed here. The possible interactions between the ubiquitin-proteasome-system, the chaperone system, the protein repair mechanisms, and other antioxidative defense strategies are highlighted.
Little is known about the regulation of signal transducer and activator of transcription (STAT) stability. Here the osmolarity-dependence of STAT3 stability, ubiquitination, Tyr 705 phosphorylation, STAT3 transactivation and c-fibrinogen (c-FBG) expression was studied in hepatoma cells. Hyper-osmolarity accelerated STAT3 degradation which was prevented by proteasome inhibitors. Hypo-osmolarity stabilized STAT3, most likely due to a decrease in STAT3 ubiquitination. Accordingly, STAT3 Tyr 705 phosphorylation, a 2 -macroglobulin promoter activity and c-FBG expression were osmosensitive. Modulation of STAT3 stability may contribute to a hydration dependence of acute phase protein expression.
One of the hallmarks of the aging process is the accumulation of oxidized proteins. Therefore, the accumulation of oxidized proteins is one of the key factors in the aging process. Oxidized proteins are normally repaired or degraded by the proteasomal system. This system is the most important intracellular protein degradation machinery, responsible for the degradation of oxidized proteins. For unknown reasons the removal of oxidized proteins is disturbed in aged cells. This leads to the accumulation of non-functional proteins. Further studies are needed for a better understanding of the changes in the proteasomal system and the interference with these changes.
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