The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan

Liu, Huaize; Ding, Jie; Köhnlein, Karl; Urban, Nadine; Ori, Alessandro; Villavicencio‐Lorini, Pablo; Walentek, Peter; Klotz, Lars‐Oliver; Hollemann, Thomas; Pfirrmann, Thorsten

doi:10.1080/15548627.2019.1695399

Cited by 51 publications

(61 citation statements)

References 55 publications

(67 reference statements)

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“…CRL4 catalyzed ubiquitination also directs AMPKγ proteolysis [121]. GID ubiquitin ligase mediates ubiquitination and degradation of AMPK as well, leading to decreased autophagy and increased mTOR activity [122]. Ubiquitination of AMPKα can be reversed by USP10 to remove the ubiquitin chain from AMPKα and promote AMPK activation [122].…”

Section: Ubiquitination Of Ampkmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

256

178

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Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment.

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Section: Ubiquitination Of Ampkmentioning

confidence: 99%

The role of ubiquitination and deubiquitination in cancer metabolism

Sun¹,

Liu²,

Yang³

2020

Mol Cancer

256

178

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“…Sex-specific methylation is also seen at this probe location in mouse muscle but in neither sheep or mouse blood (Figure 6A-B), implying that such androgen-sensitive effects in MKLN1 and other loci may be mammalian wide but certainly not ubiquitous across all tissues. Evidence for MKLN1 androgen-dependency has previously been presented (Jin et al, 2013) and MKLN1-containing complexes have been shown to regulate lifespan in Caenorhabditis elegans (Hamilton et al, 2005; Liu et al, 2019), although no links between this gene and mammalian longevity have yet been reported. ChIP-seq data demonstrates enriched AR binding at the position of this asDMP in human, as well as exhibiting high sequence conservation, DNase hypersensitivity and H3K27ac marks – the latter two of which are markers of open chromatin and indicate transcriptionally active areas (Figure 5C) (Creyghton et al, 2010; Wang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci

Sugrue

Narayan

et al. 2020

Preprint

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SUMMARYIn mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age using only DNA methylation data. These clocks have been used to identify novel factors influencing the aging rate, but few studies have examined the performance of epigenetic clocks in divergent mammalian species. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), and using 185 CpG sites can predict chronological age with a median absolute error of 5.1 months from ear punch and blood samples. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Many of these androgen sensitive demethylating sites are regulatory in nature and located in genes with known androgen-dependent regulation, such as MKLN1, LMO4 and FN1. Comparable sex-specific methylation differences in MKLN1 also exist in mouse muscle (p=0.003) but not blood, indicating that androgen dependent demethylation exists in multiple mammalian groups, in a tissue-specific manner. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

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“…Consequently, MKRN1-null mice exhibit AMPK hyperactivity in liver and adipose tissue and are protected against diet-induced metabolic syndrome, whereas lowering MKRN1 expression in obese mice reversed non-alcoholic fatty liver disease. The glucoseinduced degradation deficient (GID)-protein complex has been reported to directly polyubiquitinate α-subunits via K48 linkages, to induce both AMPK proteasomal degradation and suppress activity as protective mechanisms to down-regulate autophagy during periods of prolonged nutrient starvation [113]. Intriguingly, α-T172 phosphorylated AMPK appeared to be the preferred substrate for GID ubiquitination, suggesting significant conformational rearrangement upon activation to enhance exposure of the target α-Lys residue.…”

Section: Ubiquitinationmentioning

confidence: 99%

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

Ovens

Scott

Langendorf

et al. 2021

IJMS

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Physical exercise elicits physiological metabolic perturbations such as energetic and oxidative stress; however, a diverse range of cellular processes are stimulated in response to combat these challenges and maintain cellular energy homeostasis. AMP-activated protein kinase (AMPK) is a highly conserved enzyme that acts as a metabolic fuel sensor and is central to this adaptive response to exercise. The complexity of AMPK’s role in modulating a range of cellular signalling cascades is well documented, yet aside from its well-characterised regulation by activation loop phosphorylation, AMPK is further subject to a multitude of additional regulatory stimuli. Therefore, in this review we comprehensively outline current knowledge around the post-translational modifications of AMPK, including novel phosphorylation sites, as well as underappreciated roles for ubiquitination, sumoylation, acetylation, methylation and oxidation. We provide insight into the physiological ramifications of these AMPK modifications, which not only affect its activity, but also subcellular localisation, nutrient interactions and protein stability. Lastly, we highlight the current knowledge gaps in this area of AMPK research and provide perspectives on how the field can apply greater rigour to the characterisation of novel AMPK regulatory modifications.

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The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan

Cited by 51 publications

References 55 publications

The role of ubiquitination and deubiquitination in cancer metabolism

The role of ubiquitination and deubiquitination in cancer metabolism

Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci

Post-Translational Modifications of the Energy Guardian AMP-Activated Protein Kinase

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