Cross-talk between Two Essential Nutrient-sensitive Enzymes

Bullen, John W.; Balsbaugh, Jeremy L.; Chanda, Dipanjan; Shabanowitz, Jeffrey; Hunt, Donald F.; Neumann, Dietbert; Hart, Gerald W.

doi:10.1074/jbc.m113.523068

Cited by 160 publications

(134 citation statements)

References 32 publications

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“…Importantly, these changes are similarly evident in rat and human diabetic myocardium. It is already well known that OGT localization and catalytic activity changes in response to metabolic cues (12,56). OGT and OGA often occur in transient protein-to-protein complexes containing kinases and phosphatases (12,56).…”

Section: Discussionmentioning

confidence: 99%

“…It is already well known that OGT localization and catalytic activity changes in response to metabolic cues (12,56). OGT and OGA often occur in transient protein-to-protein complexes containing kinases and phosphatases (12,56). These include kinases and phosphatases such as AMPK (56), Ca 2+ /calmodulin-dependent protein kinase IV, p38–mitogen-activated protein kinase, protein phosphatase 1, and myosin phosphatase targeting 1, which are key regulators of cardiac metabolism and function (12).…”

Section: Discussionmentioning

confidence: 99%

“…OGT and OGA often occur in transient protein-to-protein complexes containing kinases and phosphatases (12,56). These include kinases and phosphatases such as AMPK (56), Ca 2+ /calmodulin-dependent protein kinase IV, p38–mitogen-activated protein kinase, protein phosphatase 1, and myosin phosphatase targeting 1, which are key regulators of cardiac metabolism and function (12). Although these protein interactions have not been confirmed in the heart, a recent report elegantly shows that CaMKII is O -GlcNAcylated during acute hyperglycemia and diabetes, leading to chronic activation, which contributes to diabetes cardiac mechanical dysfunction and arrhythmias (24).…”

Section: Discussionmentioning

confidence: 99%

“…These alterations are potentially relevant to the pathogenesis of diabetic systolic and diastolic dysfunction, given that transient protein-to-protein complexes regulate OGT substrate specificity (12). Because O -GlcNAcylation and phosphorylation signaling cascades have extensive cross-talk (12,56), both at the level of site occupancy and at the level of modifying enzymes, further dissecting this phenomenon in the heart would be important.…”

Section: Discussionmentioning

confidence: 99%

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Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle

Ramírez-Correa

Slawson

et al. 2015

Diabetes

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Contractile dysfunction and increased deposition of O-linked β-N-acetyl-d-glucosamine (O-GlcNAc) in cardiac proteins are a hallmark of the diabetic heart. However, whether and how this posttranslational alteration contributes to lower cardiac function remains unclear. Using a refined β-elimination/Michael addition with tandem mass tags (TMT)–labeling proteomic technique, we show that CpOGA, a bacterial analog of O-GlcNAcase (OGA) that cleaves O-GlcNAc in vivo, removes site-specific O-GlcNAcylation from myofilaments, restoring Ca2+ sensitivity in streptozotocin (STZ) diabetic cardiac muscles. We report that in control rat hearts, O-GlcNAc and O-GlcNAc transferase (OGT) are mainly localized at the Z-line, whereas OGA is at the A-band. Conversely, in diabetic hearts O-GlcNAc levels are increased and OGT and OGA delocalized. Consistent changes were found in human diabetic hearts. STZ diabetic hearts display increased physical interactions of OGA with α-actin, tropomyosin, and myosin light chain 1, along with reduced OGT and increased OGA activities. Our study is the first to reveal that specific removal of O-GlcNAcylation restores myofilament response to Ca2+ in diabetic hearts and that altered O-GlcNAcylation is due to the subcellular redistribution of OGT and OGA rather than to changes in their overall activities. Thus, preventing sarcomeric OGT and OGA displacement represents a new possible strategy for treating diabetic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle

Ramírez-Correa

Slawson

et al. 2015

Diabetes

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“…On the other hand it has been shown that both BCL2 and BECN1, key regulators of autophagy, undergo O-GlcNAcylation, in response to nutrient deprivation (58). In addition, both AKT and AMPK, key regulators of the MTORC1 complex, are also targets for O-GlcNAcylation (59;60). Taken together these observations provide strong support for a role of O-GlcNAcylation in regulating the autophagic response to stress…”

Section: Regulation Of Autophagy By O-glcnacylationmentioning

confidence: 99%

Regulation of autophagy by protein post-translational modification

Wani

Boyer-Guittaut

Dodson

et al. 2015

Laboratory Investigation

136

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Autophagy is a lysosomal mediated intracellular protein degradation process that involves ~38 autophagy related genes as well as key signaling pathways that sense cellular metabolic and redox status, and plays an important role in quality control of macromolecules and organelles. As with other major cellular pathways, autophagy proteins are subject to regulatory post-translational modification. Phosphorylation is so far the most intensively studied post-translational modification in the autophagy process, followed by ubiquitination and acetylation. An interesting and new area is also now emerging, which appears to complement these more traditional mechanisms, and includes O-GlcNAcylation and redox regulation at thiol residues. Identification of the full spectrum of post-translational modifications of autophagy proteins, and determination of their impact on autophagy will be crucial for a better understanding of autophagy regulation, its deficits in diseases, and how to exploit this process for disease therapies.

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Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

Zachara

2018

FEBS Letters

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Almost 100 years after the first descriptions of proteins conjugated to carbohydrates (mucins), several studies suggested that glycoproteins were not restricted to the serum, extracellular matrix, cell surface, or endomembrane system. In the 1980’s, key data emerged demonstrating that intracellular proteins were modified by monosaccharides of O-linked β-N-acetylglucosamine (O-GlcNAc). Subsequently, this modification was identified on thousands of proteins that regulate cellular processes as diverse as protein aggregation, localization, post-translational modifications, activity, and interactions. In this Review, we will highlight critical discoveries that shaped our understanding of the molecular events underpinning the impact of O-GlcNAc on protein function, the role that O-GlcNAc plays in maintaining cellular homeostasis, and our understanding of the mechanisms that regulate O-GlcNAc-cycling.

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Cross-talk between Two Essential Nutrient-sensitive Enzymes

Cited by 160 publications

References 32 publications

Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle

Removal of Abnormal Myofilament O-GlcNAcylation Restores Ca2+ Sensitivity in Diabetic Cardiac Muscle

Regulation of autophagy by protein post-translational modification

Critical observations that shaped our understanding of the function(s) of intracellular glycosylation (O‐GlcNAc)

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