Hexosamine Pathway Metabolites Enhance Protein Quality Control and Prolong Life

Denzel, Martin S.; Storm, Nadia; Gutschmidt, Aljona; Baddi, Ruth; Hinze, Yvonne; Jarosch, Ernst; Sommer, Thomas; Hoppe, Thorsten; Antebi, Adam

doi:10.1016/j.cell.2014.01.061

Cited by 197 publications

(224 citation statements)

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“…It has also been reported that increased HBP flux by gainof-function mutation of GFAT1 or exogenous addition of GlcNAc controls protein quality control through increased autophagy, ER-associated degradation, and proteasome activ- ity, thereby exerting cytoprotective effects in Caenorhabditis elegans disease models and extending lifespan (Fig. 3B) (66). Furthermore, we and others have recently shown that O-GlcNAc on proteins such as tau, TAK1-binding protein, ␣-synuclein, and PFK1 inhibits oligomerization or aggregation in the context of disease states (36,67,68).…”

Section: O-glcnac and Cancer Cell Survivalmentioning

confidence: 99%

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

184

145

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O-Linked ␤-N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.

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Section: O-glcnac and Cancer Cell Survivalmentioning

confidence: 99%

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

184

145

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“…Moreover, this result emphasizes that compartmentalization of stressresponse pathways does not preclude extensive cross-talk between sensors and that this communication may make it difficult at times to determine the actual location of the proteotoxic species (Liu and Chang 2008;Buchberger et al 2010;Richter et al 2010;Heldens et al 2011;Roth et al 2014). There are two other studies that make experimental inferences based on the notion that SRP-2 H302R ::YFP was aggregating within the ER instead of the cytosol (Denzel et al 2014;Hou et al 2014). First, Hou et al (2014) show that loss-of-function of the Mediator subunit, mdt-15, causes an increase in ER membrane phospholipid saturation and activation of the UPR.…”

Section: Discussionmentioning

confidence: 99%

“…While these animals expressing mutant SRP-2 could be used to study the effects of cytosolic serpin polymerization, the markedly different expression patterns, inhibitory profiles, and subcellular localization of SRP-2 compared to those of human NS/ SERPINI1 confound the ability to use these animals to model accurately the interaction between aging and ER overload in patients with the serpinopathy, FENIB. Furthermore, interesting experimental results regarding the effects of mutant SRP-2 on ER proteostasis pathways should be viewed from the perspective that this proteotoxic stress originated from within the cytosol and not the ER (Denzel et al 2014;Hou et al 2014).…”

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confidence: 99%

“…The authors conclude that this transgenic strain accumulates mutant SRP-2 in the ER and therefore serves as an invertebrate model of FENIB. Moreover, other investigators have used these transgenic animals to study the relationship between a luminal misfolded ER protein and the unfolded protein response (UPR) and ER-associated degradation (ERAD) pathways under different experimental conditions (Denzel et al 2014;Hou et al 2014). However, using colocalization studies and comparisons to the canonical serpinopathy caused by ATZ, we show unequivocally that wild-type and mutant SRP-2 reside in the cytosol and not in the ER.…”

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confidence: 99%

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The Aggregation-Prone Intracellular Serpin SRP-2 Fails to Transit the ER inCaenorhabditis elegans

Silverman¹,

Cummings²,

O’Reilly³

et al. 2015

Genetics

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Familial encephalopathy with neuroserpin inclusions bodies (FENIB) is a serpinopathy that induces a rare form of presenile dementia. Neuroserpin contains a classical signal peptide and like all extracellular serine proteinase inhibitors (serpins) is secreted via the endoplasmic reticulum (ER)-Golgi pathway. The disease phenotype is due to gain-of-function missense mutations that cause neuroserpin to misfold and aggregate within the ER. In a previous study, nematodes expressing a homologous mutation in the endogenous Caenorhabditis elegans serpin, srp-2, were reported to model the ER proteotoxicity induced by an allele of mutant neuroserpin. Our results suggest that SRP-2 lacks a classical N-terminal signal peptide and is a member of the intracellular serpin family. Using confocal imaging and an ER colocalization marker, we confirmed that GFP-tagged wild-type SRP-2 localized to the cytosol and not the ER. Similarly, the aggregationprone SRP-2 mutant formed intracellular inclusions that localized to the cytosol. Interestingly, wild-type SRP-2, targeted to the ER by fusion to a cleavable N-terminal signal peptide, failed to be secreted and accumulated within the ER lumen. This ER retention phenotype is typical of other obligate intracellular serpins forced to translocate across the ER membrane. Neuroserpin is a secreted protein that inhibits trypsinlike proteinase. SRP-2 is a cytosolic serpin that inhibits lysosomal cysteine peptidases. We concluded that SRP-2 is neither an ortholog nor a functional homolog of neuroserpin. Furthermore, animals expressing an aggregation-prone mutation in SRP-2 do not model the ER proteotoxicity associated with FENIB.

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“…[6][7][8] As the body ages, damaged organelles and abnormal proteins accumulate, disrupting cellular homeostasis. [9][10][11] A system for eliminating damaged organelles, proteins, and intracellular pathogens is critical for maintaining cellular homeostasis as the body ages. In recent years, it has become evident that autophagy plays a pivotal role in this regard.…”

Section: )mentioning

confidence: 99%

The Impact of Autophagy on Cardiovascular Senescence and Diseases

et al. 2017

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SummaryThe risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.(Int Heart J 2017; 58: 666-673) Key words: Cardiovascular disease, Aging, Heart failure, Atherosclerosis T he human life span has significantly increased over recent decades and is expected to increase even further. Consequently, the prevalence of agerelated cardiovascular disease is also increasing. 1) Many risk factors for cardiovascular disease, such as hypertension, diabetes mellitus, dyslipidemia, and metabolic syndrome, emerge with age, and cardiovascular disease is the leading cause of chronic disability, morbidity, and mortality among the elderly. 2,3)The aging heart is associated with increases in left ventricular wall thickness, stiffness, and chamber size, as well as changes in the diastolic filling pattern, which can lead to cardiac dysfunction. 4,5) Age-related loss of vascular elasticity and stiffness increases cardiac after-load in the elderly. [6][7][8] As the body ages, damaged organelles and abnormal proteins accumulate, disrupting cellular homeostasis.9-11) A system for eliminating damaged organelles, proteins, and intracellular pathogens is critical for maintaining cellular homeostasis as the body ages. In recent years, it has become evident that autophagy plays a pivotal role in this regard. 12,13) In particular, autophagy functions as part of a pathway that delivers cytoplasmic substrates to lysosomes for subsequent degradation and removal. Autophagy modulates homeostasis and the body's response to stress, including energy deprivation in the heart, and altered autophagy is related to cardiovascular aging and disease.14-18) Because autophagy attenuates with age, interventions that increase autophagy may in turn reduce agerelated cardiovascular disease, prolonging the lifespan. 19-21)On the other hand, overexpression of autophagy in the heart can induce atrophy of cardiomyocytes, increasing the risk of ischemia-reperfusion injury. 22,23) This review summarizes our current understanding of the close relationship between autophagy and cardiovascular senescence. Three Types of AutophagyAutophagy is classified into 3 subtypes: macr...

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Hexosamine Pathway Metabolites Enhance Protein Quality Control and Prolong Life

Cited by 197 publications

References 50 publications

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

The Aggregation-Prone Intracellular Serpin SRP-2 Fails to Transit the ER inCaenorhabditis elegans

The Impact of Autophagy on Cardiovascular Senescence and Diseases

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