Deubiquitination and Activation of AMPK by USP10

Deng, Min; Xu, Yang; Qin, Bo; Liu, Tongzheng; Zhang, Haoxing; Guo, Wei; Lee, Seung Baek; Kim, Jung Jin; Yuan, Jian; Pei, Huadong; Wang, Liewei M; Lou, Zhenkun

doi:10.1016/j.molcel.2016.01.010

Cited by 116 publications

(111 citation statements)

References 43 publications

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“…In parallel with downregulation of factors involved in MPS, our data also indicate an upregulation of AMPK, suggesting that CRP may involve an induction of cellular energy stress [40]. It has previously been shown that under conditions of cellular energy stress, increased phosphorylation of the AMPK leads to the suppression of mTORC1 activity [41][42][43]. Our study also reveals an upregulation of the two AMPK downstream targets, raptor and ACC-β.…”

Section: Discussionsupporting

confidence: 80%

Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly

Wåhlin-Larsson

Wilkinson

Strandberg

et al. 2017

Cell Physiol Biochem

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Background/Aims: Mechanisms underlying the relationship between systemic inflammation and age-related decline in muscle mass are poorly defined. The purpose of this work was to investigate the relationship between the systemic inflammatory marker CRP and muscle mass in elderly and to identify mechanisms by which CRP mediates its effects on skeletal muscle, in-vitro. Methods: Muscle mass and serum CRP level were determined in a cohort of 118 older women (67±1.7 years). Human muscle cells were differentiated into myotubes and were exposed to CRP. The size of myotubes was determined after immunofluorescent staining using troponin. Muscle protein synthesis was assessed using stable isotope tracers and key signalling pathways controlling protein synthesis were determined using western-blotting. Results: We observed an inverse relationship between circulating CRP level and muscle mass (β= -0.646 (95% CI: -0.888, -0.405) p<0.05) and demonstrated a reduction (p < 0.05) in the size of human myotubes exposed to CRP for 72 h. We next showed that this morphological change was accompanied by a CRP-mediated reduction (p < 0.05) in muscle protein fractional synthetic rate of human myotubes exposed to CRP for 24 h. We also identified a CRPmediated increased phosphorylation (p<0.05) of regulators of cellular energy stress including AMPK and downstream targets, raptor and ACC-β, together with decreased phosphorylation of Akt and rpS6, which are important factors controlling protein synthesis. Conclusion: This work established for the first time mechanistic links by which chronic elevation of CRP can contribute to age-related decline in muscle function.

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Section: Discussionsupporting

confidence: 80%

Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly

Wåhlin-Larsson

Wilkinson

Strandberg

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

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“…Hence, AMPKdependent phosphorylation of USP10 establishes a positive-feedback loop for enhancing AMPK activity during conditions of energy stress. Consistent with such a scenario, USP10 depletion in mouse liver leads to metabolic defects such as an increase in triglyceride and cholesterol content (Deng et al, 2016). By contrast, USP37 is activated in a cell cycle-specific manner by CDK2-mediated phosphorylation at Ser628 (Huang et al, 2011).…”

Section: Phosphorylationmentioning

confidence: 75%

“…Phosphorylation at Ser76 by AMPactivated protein kinase (AMPK) activates USP10, which can then remove Lys63-linked polyubiquitin from the activation loop of AMPK (Deng et al, 2016). This in turn enables liver kinase B1 (LKB1; also known as STK11)-mediated phosphorylation of AMPK at Thr172, leading to further AMPK activation.…”

Section: Phosphorylationmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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“…To date, USP10 has not been implicated in proteasome function in mammalian cells. However, like UBP3 in yeast, USP10 has been reported to regulate numerous cellular functions, including controlling the induction of autophagy, sensing energy stress via AMPK, and regulating the stability of p53 (Yuan et al 2010;Liu et al 2011;Deng et al 2016). USP10 can thus also be considered a pleiotropic hub protein that, like UBP3, impacts the fitness of aneuploid mammalian cells in multiple ways.…”

Section: The Ubp3 Homolog Usp10 Confers Aneuploidy Tolerance In Humanmentioning

confidence: 99%

The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance

et al. 2016

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Aneuploidy-or an unbalanced karyotype in which whole chromosomes are gained or lost-causes reduced fitness at both the cellular and organismal levels but is also a hallmark of human cancers. Aneuploidy causes a variety of cellular stresses, including genomic instability, proteotoxic and oxidative stresses, and impaired protein trafficking. The deubiquitinase Ubp3, which was identified by a genome-wide screen for gene deletions that impair the fitness of aneuploid yeast, is a key regulator of aneuploid cell homeostasis. We show that deletion of UBP3 exacerbates both karyotype-specific phenotypes and global stresses of aneuploid cells, including oxidative and proteotoxic stress. Indeed, Ubp3 is essential for proper proteasome function in euploid cells, and deletion of this deubiquitinase leads to further proteasome-mediated proteotoxicity in aneuploid yeast. Notably, the importance of UBP3 in aneuploid cells is conserved. Depletion of the human homolog of UBP3, USP10, is detrimental to the fitness of human cells upon chromosome missegregation, and this fitness defect is accompanied by autophagy inhibition. We thus used a genome-wide screen in yeast to identify a guardian of aneuploid cell fitness conserved across species. We propose that interfering with Ubp3/USP10 function could be a productive avenue in the development of novel cancer therapeutics.

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Deubiquitination and Activation of AMPK by USP10

Cited by 116 publications

References 43 publications

Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly

Mechanistic Links Underlying the Impact of C-Reactive Protein on Muscle Mass in Elderly

Mechanisms of regulation and diversification of deubiquitylating enzyme function

The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance

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