TCF11 at the crossroads of oxidative stress and the ubiquitin proteasome system

Koch, Annett; Steffen, Janos; Krüger, Elke

doi:10.4161/cc.10.8.15327

Cited by 19 publications

(12 citation statements)

References 59 publications

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“…The ubiquitin proteasome system (UPS) is a fundamental mechanism for degrading oxidant-damaged proteins, while proteasomal dysfunction is associated with a variety of human disorders, including diabetes and PD (Costes et al, 2011, Koch et al, 2011, Geisler et al, 2014). TCF11 (long isoform of Nrf1) is a key regulator for proteasome formation, and was recently discovered to transcriptionally control proteasomal degradation via an endoplasmic reticulum-associated protein degradation (ERAD)-dependent feedback loop (Steffen et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats

Shuler

Raider

et al. 2015

Brain Research

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Diet-induced obesity can increase the risk for developing age-related neurodegenerative diseases including Parkinson’s disease (PD). Increasing evidence suggests that mitochondrial and proteasomal mechanisms are involved in both insulin resistance and PD. The goal of this study was to determine whether diet intervention could influence mitochondrial or proteasomal protein expression and vulnerability to 6-Hydroxydopamine (6-OHDA)-induced nigrostriatal dopamine (DA) depletion in rats’ nigrostriatal system. After a 3 month high-fat diet regimen, we switched one group of rats to a low-fat diet for 3 months (HF-LF group), while the other half continued with the high-fat diet (HF group). A chow group was included as a control. Three weeks after unilateral 6-OHDA lesions, HF rats had higher fasting insulin levels and higher Homeostasis model assessment of insulin resistance (HOMA-IR), indicating insulin resistance. HOMA-IR was significantly lower in HF-LF rats than HF rats, indicating that insulin resistance was reversed by switching to a low-fat diet. Compared to the Chow group, the HF group exhibited significantly greater DA depletion in the substantia nigra but not in the striatum. DA depletion did not differ between the HF-LF and HF group. Proteins related to mitochondrial function (such as AMPK, PGC-1α), and to proteasomal function (such as TCF11/Nrf1) were influenced by diet intervention, or by 6-OHDA lesion. Our findings suggest that switching to a low-fat diet reverses the effects of a high-fat diet on systemic insulin resistance, and mitochondrial and proteasomal function in the striatum. Conversely, they suggest that the effects of the high-fat diet on nigrostriatal vulnerability to 6-OHDA-induced DA depletion persist.

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Section: Discussionmentioning

confidence: 99%

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats

Shuler

Raider

et al. 2015

Brain Research

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“…The Nrf2 activator oltipraz, which was demonstrated to attenuate CHPH in mice [38], can regulate PSMB6 expression [39]. TCF11, which plays an important role in COPD, is a key regulator for UPS [40] and 26S PSMB6 [41].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis Reveals that Proteasome Subunit Beta 6 Is Involved in Hypoxia-Induced Pulmonary Vascular Remodeling in Rats

Wang

Xing

et al. 2013

PLoS ONE

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BackgroundChronic hypoxia (CH) is known to be one of the major causes of pulmonary hypertension (PH), which is characterized by sustained elevation of pulmonary vascular resistance resulting from vascular remodeling. In this study, we investigated whether the ubiquitin proteasome system (UPS) was involved in the mechanism of hypoxia-induced pulmonary vascular remodeling. We isolated the distal pulmonary artery (PA) from a previously defined chronic hypoxic pulmonary hypertension (CHPH) rat model, performed proteomic analyses in search of differentially expressed proteins belonging to the UPS, and subsequently identified their roles in arterial remodeling.ResultsTwenty-two proteins were differently expressed between the CH and normoxic group. Among them, the expression of proteasome subunit beta (PSMB) 1 and PSMB6 increased after CH exposure. Given that PSMB1 is a well-known structural subunit and PSMB6 is a functional subunit, we sought to assess whether PSMB6 could be related to the multiple functional changes during the CHPH process. We confirmed the proteomic results by real-time PCR and Western blot. With the increase in quantity of the active subunit, proteasome activity in both cultured pulmonary artery smooth muscle cells (PASMCs) and isolated PA from the hypoxic group increased. An MTT assay revealed that the proteasome inhibitor MG132 was able to attenuate the hypoxia-induced proliferation of PASMC in a dose-dependent manner. Knockdown of PSMB6 using siRNA also prevented hypoxia-induced proliferation.ConclusionThe present study revealed the association between increased PSMB6 and CHPH. CH up-regulated proteasome activity and the proliferation of PASMCs, which may have been related to increased PSMB6 expression and the subsequently enhanced functional catalytic sites of the proteasome. These results suggested an essential role of the proteasome during CHPH development, a novel finding requiring further study.

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“…11,21,26,27 These characteristics of NEDD8 might be biologically significant, considering that changes in rates of degradation could give more opportunities for refolding of misfolded proteins, which is an energetically favorable mechanism in higher eukaryotes. 28,29 Alternatively, the incorporation of NEDD8 within ubiquitin chains under stress could be part of a mechanism to prevent further depletion of ubiquitin and to restore the initial ubiquitin levels.…”

Section: Disclosure Of Potential Conflicts Of Interestmentioning

confidence: 99%

The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions

Leidecker¹,

Matić²,

Mahata³

et al. 2012

Cell Cycle

112

124

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Modification of proteins with ubiquitin and ubiquitin-like molecules is involved in the regulation of almost every biological process. Historically, each conjugation pathway has its unique set of E1, E2 and E3 enzymes that lead to activation and conjugation of their cognate molecules. Here, we present the unexpected finding that under stress conditions, the ubiquitin E1 enzyme Ube1 mediates conjugation of the ubiquitin-like molecule NEDD8. Inhibition of the 26S proteasome, heat shock and oxidative stress cause a global increase in NEDDylation. Surprisingly, this does not depend on the NEDD8 E1-activating enzyme, but rather on Ube1. A common event in the tested stress conditions is the depletion of "free" ubiquitin. A decrease in "free" ubiquitin levels in the absence of additional stress is sufficient to stimulate NEDDylation through Ube1. Further analysis on the NEDD8 proteome shows that the modified NEDDylated proteins are simultaneously ubiquitinated. Mass spectrometry on the complex proteome under stress reveals the existence of mixed chains between NEDD8 and ubiquitin. We further show that NEDDylation of the p53 tumor suppressor upon stress is mediated mainly through Ube1. Our studies reveal an unprecedented interplay between NEDD8 and ubiquitin pathways operating in diverse cellular stress conditions.

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TCF11 at the crossroads of oxidative stress and the ubiquitin proteasome system

Cited by 19 publications

References 59 publications

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats

Effects of discontinuing a high-fat diet on mitochondrial proteins and 6-hydroxydopamine-induced dopamine depletion in rats

Proteomic Analysis Reveals that Proteasome Subunit Beta 6 Is Involved in Hypoxia-Induced Pulmonary Vascular Remodeling in Rats

The ubiquitin E1 enzyme Ube1 mediates NEDD8 activation under diverse stress conditions

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