mTORC1 signaling activates NRF1 to increase cellular proteasome levels

Zhang, Yinan; Manning, Brendan D.

doi:10.1080/15384101.2015.1044188

Cited by 79 publications

(73 citation statements)

References 71 publications

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“…As published 1 , TSC2-deficient cells with activated mTORC1 displayed enhanced rates of protein turnover relative to rapamycin-treated or TSC2-expressing cells, where mTORC1 is inactive. The differences are most evident at the later time points (>5 h), consistent with the NRF1-dependent transcriptional mechanism delineated in our study 1 and discussed in detail else where 2 . Thus, the discrepancy with Zhao et al’s communicated findings has nothing to do with the assay, but rather is due to differences in the chosen culture conditions.…”

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confidence: 90%

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Zhang

Manning

2016

Nature

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supporting

confidence: 90%

“…We stand by our conclusions that mTORC1 activation promotes the production of proteasomes leading to enhanced proteasome-mediated protein turnover through an increase in NRF1 1,2 , a transcription factor now established in multiple independent studies to control cellular proteasome levels 1–8 .…”

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Zhang

Manning

2016

Nature

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“…Alternatively, when available, the analysis of CNOT6 and CNOT6L +/− heterozygous mice would also shed some light on possible functions of CNOT in aging. On the other hand, it is also possible that changes in proteasomal function in slow‐aging mice could contribute to the elevation of MGMT, NDRG1, and CNOT6L (Wang & Miller, 2012; Zhang et al ., 2014; Zhang & Manning, 2015). …”

Section: Discussionmentioning

confidence: 99%

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Dominick

Bowman

et al. 2016

Aging Cell

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SummaryStudies of the mTOR pathway have prompted speculation that diminished mTOR complex‐1 (mTORC1) function may be involved in controlling the aging process. Our previous studies have shown diminished mTORC1 activity in tissues of three long‐lived mutant mice: Snell dwarf mice, growth hormone receptor gene disrupted mice (GHRKO), and in this article, mice deficient in the pregnancy‐associated protein‐A (PAPPA‐KO). The ways in which lower mTOR signals slow aging and age‐related diseases are, however, not well characterized. Here, we show that Snell, GHKRO, and PAPPA‐KO mice express high levels of two proteins involved in DNA repair, O‐6‐methylguanine‐DNA methyltransferase (MGMT) and N‐myc downstream‐regulated gene 1 (NDRG1). Furthermore, we report that lowering mTOR enhances MGMT and NDRG1 protein expression via post‐transcriptional mechanisms. We show that the CCR4‐NOT complex, a post‐transcriptional regulator of gene expression, is downstream of the mTORC1 pathway and may be responsible for the upregulation of MGMT and NDRG1 in all three varieties of long‐lived mice. Our data thus suggest a novel link between DNA repair and mTOR signaling via post‐transcriptional regulation involving specific alteration in the CCR4‐NOT complex, whose modulation could control multiple aspects of the aging process.

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“…Ubiquitin-specific protease 15 (USP15) has been suggested to activate Nrf1 function in the nucleus by stabilizing Nrf1 through its deubiquitination[165]. Furthermore, activation of mTORC1 signaling stimulates Nrf1 activity, leading to increased levels of proteasomes[166]. However, the connection between Nrf1/Nrf2 and TORC1-mediated regulation of proteasome assembly chaperones remains unknown.…”

Section: Regulation Of Proteasome Expressionmentioning

confidence: 99%

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

304

280

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The eukaryotic 26S proteasome is a large multi-subunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle (RP) and the 20S core particle (CP). Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the RP is to recognize, unfold, deubiquitylate and translocate substrates into the CP, which contains the proteolytic sites of the proteasome. Given the abundance and subunit complexity of the proteasome, the assembly of this ~2.5 MDa complex must be carefully orchestrated to ensure its correct formation. In recent years, significant advances have been made in the understanding of proteasome assembly, structure and function. Technical advances in cryo-electron microscopy have resulted in a series of atomic cryo-EM structures of both human and yeast 26S proteasomes. These structures have illuminated new intricacies and dynamics of the proteasome. In this review, we focus on the mechanisms of proteasome assembly, particularly in light of recent structural information.

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mTORC1 signaling activates NRF1 to increase cellular proteasome levels

Cited by 79 publications

References 71 publications

Zhang & Manning reply

Zhang & Manning reply

mTOR regulates the expression of DNA damage response enzymes in long‐lived Snell dwarf, GHRKO, and PAPPA‐KO mice

Proteasome Structure and Assembly

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