Decreased Proteasome-Mediated Degradation in T Cells from the Elderly: A Role in Immune Senescence

Ponnappan, Usha; Zhong, Mingzheng; Trebilcock, Gina Uken

doi:10.1006/cimm.1998.1418

Cited by 93 publications

(51 citation statements)

References 26 publications

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“…Previous studies have clearly demonstrated that aging is accompanied by deficits in activation-induced T cell responses such as of IL-2R expression, IL-2 secretion and proliferation [1][2][3][4][5][6][7][8]. We have previously demonstrated that decreased induction of the transcription factor NFκB, contributes to lowered induction of IL-2R during aging [4,9].…”

Section: Introductionmentioning

confidence: 85%

“…We have previously demonstrated that decreased induction of the transcription factor NFκB, contributes to lowered induction of IL-2R during aging [4,9]. Additional studies demonstrated this decline in NFκB to be attributable to a central defect in the proteolytic activity of the 26S proteasome [4,7,10].…”

Section: Introductionmentioning

confidence: 94%

“…T cells were lysed using proteasome lysis buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl 2 , and 250 mM sucrose followed by centrifugation at 12,000×g for 10 min [4]. The supernatant was then subjected to ultra centrifugation at 100,000×g for 1 h at 4 ο C. 20S proteasome-enriched fraction (50 μg protein) was incubated in 200 μl of assay buffer containing 50 mM Tris-HCl (pH 7.8), 10 mM MgCl 2 , and 1 mM dithiothreitol (DTT) for 1 h at 37°C in the absence of ATP.…”

Section: Determination Of 20s Proteasome Catalytic Activitiesmentioning

confidence: 99%

“…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]. Indeed, both 20S and 26S proteasomes show age-related decline in their enzymatic activities in most cell types ranging from T lymphocytes to neurons [4,10,[20][21][22]. Studies by Chondrogianni et al revealed that, while the inhibition of proteasome induced a senescent phenotype, stable expression of β 1 or β 5 catalytic subunits in WI38 immortalized fibroblasts and HL60 leukemic cell line results in increased proteasomal activities and cell survival following treatment with oxidants [23].…”

Section: Introductionmentioning

confidence: 99%

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Redox regulation of the proteasome in T lymphocytes during aging

Das

Ponnappan

2007

Free Radical Biology and Medicine

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Proteasome is a major cellular organelle responsible for the regulated turn-over of both normal and misfolded proteins. Recent reports from our laboratory have implicated lowered proteasomal chymotryptic activity to be responsible for decreased induction of the transcription factor NFκB in T lymphocytes during aging. In this study, we have further analyzed the basis for this decline in proteasomal function, by focusing on the role of oxidative stress. Upon exposure to the pro-oxidant BSO, both ATP-stimulatable 26S, as well as ATP-independent 20S proteasomal catalytic activity could be down-regulated in T cells from young donors, mimicking the decline observed in T cells from the elderly. Loss in these catalytic activities, following exposure to pro-oxidant stimulus also resulted in a decline in both activation-induced proliferation as well as degradation of the inhibitor IκBα, with concomitant increase in the accumulation of carbonylated proteins, mimicking responses seen in T cells from the elderly. Pretreatment with an antioxidant, NAC could override pro-oxidantmediated, but not age-associated decrease in both 20S proteasomal activities. These results suggest that the decrease in proteasomal activities observed during aging may be secondary to oxidative stress and underlie immune senescence.

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Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 94%

Section: Determination Of 20s Proteasome Catalytic Activitiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Redox regulation of the proteasome in T lymphocytes during aging

Das

Ponnappan

2007

Free Radical Biology and Medicine

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“…Such a decline of proteasome activity would therefore be expected to promote the accumulation of oxidized protein with age. Indeed, as first shown by us for the peptidylglutamyl peptide hydrolase activity of proteasome purified from rat liver [30], an age-related decrease of at least certain proteasome peptidase activities, has been since reported for human keratinocytes, human fibroblasts, human eye lens, human lymphocytes, rat liver, rat cardiomycytes, rat brain and rat skeletal muscle [31][32][33][34][35][36][37][38][39][40][41][42]. Our initial finding of decreased peptidylglutamyl peptide hydrolase activity of proteasome purified from the liver of old rats was in favor of its specific inactivation.…”

Section: Impaired Removal Of Oxidized Proteins During Ageingmentioning

confidence: 99%

Oxidized protein degradation and repair in ageing and oxidative stress

2006

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Cellular ageing is characterized by the accumulation of oxidatively modified proteins which may be due to increased protein damage and/or decreased elimination of oxidized protein.Since the proteasome is in charge of protein turnover and removal of oxidized protein, its fate during ageing and upon oxidative stress has received special attention, and evidence has been provided for an age-related impairment of proteasome function. However, proteins when oxidized at the level of sulfur-containing amino acids can also be repaired. Therefore, the fate of the methionine sulfoxide reductase system during ageing has also been addressed as well as its role in protection against oxidative stress.

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Heat Shock Response and Ageing: Mechanisms and Applications

Verbeke

2001

Cell Biology International

205

164

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Ageing is associated with a decrease in the ability of cells to cope with environmental challenges. This is due partly to the attenuation of a primordial stress response, the so-called heat shock (HS) response, which induces the expression of heat shock proteins (HSPs), composed of chaperones and proteases. The attenuation of the HS response during ageing may be responsible for the accumulation of damaged proteins as well as abnormal regulation of cell death. Maintenance of the HS response by repeated mild heat stress causes anti-ageing hormetic effects on cells and organisms. Here, we describe the molecular mechanism and the state of the HS response as well as the role of specific HSPs during ageing, and discuss the possibility of hormetic modulation of ageing and longevity by repeated mild stress.

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Decreased Proteasome-Mediated Degradation in T Cells from the Elderly: A Role in Immune Senescence

Cited by 93 publications

References 26 publications

Redox regulation of the proteasome in T lymphocytes during aging

Redox regulation of the proteasome in T lymphocytes during aging

Oxidized protein degradation and repair in ageing and oxidative stress

Heat Shock Response and Ageing: Mechanisms and Applications

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