NADH Binds and Stabilizes the 26S Proteasomes Independent of ATP

Tsvetkov, Peter; Myers, Nadav; Eliav, Raz; Adamovich, Yaarit; Hagai, Tzachi; Adler, Julia; Navon, Ami; Shaul, Yosef

doi:10.1074/jbc.m113.537175

Cited by 36 publications

(32 citation statements)

References 40 publications

(35 reference statements)

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“…The Lo19S state is achieved by reduced gene expression of any one 19S subunit. However, other post-translational events can regulate the levels of intact 26S proteasomes including oxidative stress (Wang et al, 2010), NADH/NAD + balance (Cho-Park and Steller, 2013;Tsvetkov et al, 2014), post-transcriptional regulation (Lokireddy et al, 2015;Myeku et al, 2016) and chaperone-mediated assembly (Kaneko et al, 2009;Rousseau and Bertolotti, 2016). Many of these processes are also associated with the cell metabolic state, which suggests that the dynamic interaction between metabolism and protein breakdown mediated by the proteasome could extend beyond transcriptional regulation of 19S subunits.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Tsvetkov

Detappe

Cai

et al. 2018

Preprint

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SUMMARYThe mechanisms used by cancer cells to resist the severe disruption in protein homeostasis caused by proteasome inhibitors remain obscure. Here, we show this resistance correlates with a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS). Employing small molecule screens, we identified a striking overlap between compounds that preferentially impede the growth of proteasome inhibitor-resistant cancer cells and those that block the growth of high OXPHOS cells. Elesclomol potently exhibits both characteristics. Using genome-wide CRISPR/Cas9-based screening, in vitro validation and NMR spectroscopy we identify mitochondrial protein ferredoxin 1 (FDX1), a critical component of mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, as the primary target of elesclomol. In a mouse model of multiple myeloma, inhibition of FDX1 with elesclomol significantly attenuated the emergence of proteasome inhibitor-resistance and markedly prolonged survival. Our work reveals that the mitochondrial Fe-S cluster pathway is a targetable vulnerability in cancers that are resistant to increased proteotoxic burden.

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Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Tsvetkov

Detappe

Cai

et al. 2018

Preprint

Self Cite

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“…These multiple changes are important in signaling and cell death pathways as the 26S proteasome is the master controller of multiple cellular functions through controlled protein degradation. NADH/NAD + plays a key role in the proteasome function as NADH maintains normal proteasome levels (43). Nrf1 and Nrf2 are involved in the resynthesis of proteasome subunits after oxidative stress and their recovery.…”

Section: Nrf2 Involvement In the Early Antioxidant Responsementioning

confidence: 99%

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

2018

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There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular “DNA-damage response”, including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early-versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.

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“…Although its detection may be simply result of an abundance of the enzyme, it might also be possible that changes in redox status of NADH may play a key role in activating this chaperone response. This possibility is supported by recent finding that NADH binds to the 26S proteasome without ATP (39) and so could be a part of a larger chaperone-proteasome complex.…”

Section: Resultsmentioning

confidence: 69%

A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition

Rodriguez

Osmulski

Pierce

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The naked mole-rat maintains robust proteostasis and high levels of proteasome-mediated proteolysis for most of its exceptional (~31y) life span. Here, we report that the highly active proteasome from the naked mole-rat liver resists attenuation by a diverse suite of proteasome-specific small molecule inhibitors. Moreover, mouse, human, and yeast proteasomes exposed to the proteasome-depleted, naked mole-rat cytosolic fractions, recapitulate the observed inhibition resistance, and mammalian proteasomes also show increased activity. Gel filtration coupled with mass spectrometry and atomic force microscopy indicates that these traits are supported by a protein factor that resides in the cytosol. This factor interacts with the proteasome and modulates its activity. Although HSP72 and HSP40 (Hdj1) are among the constituents of this factor, the observed phenomenon, such as increasing peptidase activity and protecting against inhibition cannot be reconciled with any known chaperone functions. This novel function may contribute to the exceptional protein homeostasis in the naked mole-rat and allow it to successfully defy aging.

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NADH Binds and Stabilizes the 26S Proteasomes Independent of ATP

Cited by 36 publications

References 40 publications

Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Inhibition of mitochondrial ferredoxin 1 (FDX1) prevents adaptation to proteotoxic stress

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

A cytosolic protein factor from the naked mole-rat activates proteasomes of other species and protects these from inhibition

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