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Ma Z, Chalkley RJ, Vosseller K. Hyper-O-GlcNAcylation activates nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling through interplay with phosphorylation and acetylation. The Journal of biological chemistry 2017 292(22) 28416608
Abstract:
O-GlcNAcylation is the covalent addition of an O-linked β-N-acetylglucosamine (O-GlcNAc) sugar moiety to hydroxyl groups of serine/threonine residues of cytosolic and nuclear proteins. O-GlcNAcylation, analogous to phosphorylation, plays critical roles in gene expression through direct modification of transcription factors, such as NF-κB. Aberrantly increased NF-κB O-GlcNAcylation has been linked to NF-κB constitutive activation and cancer development. Therefore, it is of a great biological and clinical significance to dissect the molecular mechanisms that tune NF-κB activity. Recently, we and others have shown that O-GlcNAcylation affects the phosphorylation and acetylation of NF-κB subunit p65/RelA. However, the mechanism of how O-GlcNAcylation activates NF-κB signaling through phosphorylation and acetylation is not fully understood. In this study, we mapped O-GlcNAcylation sites of p65 at Thr-305, Ser-319, Ser-337, Thr-352, and Ser-374. O-GlcNAcylation of p65 at Thr-305 and Ser-319 increased CREB-binding protein (CBP)/p300-dependent activating acetylation of p65 at Lys-310, contributing to NF-κB transcriptional activation. Moreover, elevation of O-GlcNAcylation by overexpression of OGT increased the expression of p300, IKKα, and IKKβ and promoted IKK-mediated activating phosphorylation of p65 at Ser-536, contributing to NF-κB activation. In addition, we also identified phosphorylation of p65 at Thr-308, which might impair the O-GlcNAcylation of p65 at Thr-305. These results indicate mechanisms through which both non-pathological and oncogenic O-GlcNAcylation regulate NF-κB signaling through interplay with phosphorylation and acetylation.
O-GlcNAc proteins:
TF65
Species: Homo sapiens
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Skorobogatko Y, Landicho A, Chalkley RJ, Kossenkov AV, Gallo G, Vosseller K. O-linked β-N-acetylglucosamine (O-GlcNAc) site thr-87 regulates synapsin I localization to synapses and size of the reserve pool of synaptic vesicles. The Journal of biological chemistry 2014 289(6) 24280219
Abstract:
O-GlcNAc is a carbohydrate modification found on cytosolic and nuclear proteins. Our previous findings implicated O-GlcNAc in hippocampal presynaptic plasticity. An important mechanism in presynaptic plasticity is the establishment of the reserve pool of synaptic vesicles (RPSV). Dynamic association of synapsin I with synaptic vesicles (SVs) regulates the size and release of RPSV. Disruption of synapsin I function results in reduced size of the RPSV, increased synaptic depression, memory deficits, and epilepsy. Here, we investigate whether O-GlcNAc directly regulates synapsin I function in presynaptic plasticity. We found that synapsin I is modified by O-GlcNAc during hippocampal synaptogenesis in the rat. We identified three novel O-GlcNAc sites on synapsin I, two of which are known Ca(2+)/calmodulin-dependent protein kinase II phosphorylation sites. All O-GlcNAc sites mapped within the regulatory regions on synapsin I. Expression of synapsin I where a single O-GlcNAc site Thr-87 was mutated to alanine in primary hippocampal neurons dramatically increased localization of synapsin I to synapses, increased density of SV clusters along axons, and the size of the RPSV, suggesting that O-GlcNAcylation of synapsin I at Thr-87 may be a mechanism to modulate presynaptic plasticity. Thr-87 is located within an amphipathic lipid-packing sensor (ALPS) motif, which participates in targeting of synapsin I to synapses by contributing to the binding of synapsin I to SVs. We discuss the possibility that O-GlcNAcylation of Thr-87 interferes with folding of the ALPS motif, providing a means for regulating the association of synapsin I with SVs as a mechanism contributing to synapsin I localization and RPSV generation.
O-GlcNAc proteins:
SYN1, SYN1, SYN1
Ma Z, Vocadlo DJ, Vosseller K. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells. The Journal of biological chemistry 2013 288(21) 23592772
Abstract:
Cancer cell metabolic reprogramming includes a shift in energy production from oxidative phosphorylation to less efficient glycolysis even in the presence of oxygen (Warburg effect) and use of glutamine for increased biosynthetic needs. This necessitates greatly increased glucose and glutamine uptake, both of which enter the hexosamine biosynthetic pathway (HBP). The HBP end product UDP-N-acetylglucosamine (UDP-GlcNAc) is used in enzymatic post-translational modification of many cytosolic and nuclear proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). Here, we observed increased HBP flux and hyper-O-GlcNAcylation in human pancreatic ductal adenocarcinoma (PDAC). PDAC hyper-O-GlcNAcylation was associated with elevation of OGT and reduction of the enzyme that removes O-GlcNAc (OGA). Reducing hyper-O-GlcNAcylation had no effect on non-transformed pancreatic epithelial cell growth, but inhibited PDAC cell proliferation, anchorage-independent growth, orthotopic tumor growth, and triggered apoptosis. PDAC is supported by oncogenic NF-κB transcriptional activity. The NF-κB p65 subunit and upstream kinases IKKα/IKKβ were O-GlcNAcylated in PDAC. Reducing hyper-O-GlcNAcylation decreased PDAC cell p65 activating phosphorylation (S536), nuclear translocation, NF-κB transcriptional activity, and target gene expression. Conversely, mimicking PDAC hyper-O-GlcNAcylation through pharmacological inhibition of OGA suppressed suspension culture-induced apoptosis and increased IKKα and p65 O-GlcNAcylation, accompanied by activation of NF-κB signaling. Finally, reducing p65 O-GlcNAcylation specifically by mutating two p65 O-GlcNAc sites (T322A and T352A) attenuated the induction of PDAC cell anchorage-independent growth. Our data indicate that hyper-O-GlcNAcylation is anti-apoptotic and contributes to NF-κB oncogenic activation in PDAC.
O-GlcNAc proteins:
IKKA, TF65
Species: Homo sapiens
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Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nature chemical biology 2012 8(4) 22366723
Abstract:
Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence tau phosphorylation in certain cases. We therefore speculated that increasing tau O-GlcNAc could be a strategy to hinder pathological tau-induced neurodegeneration. Here we found that treatment of hemizygous JNPL3 tau transgenic mice with an O-GlcNAcase inhibitor increased tau O-GlcNAc, hindered formation of tau aggregates and decreased neuronal cell loss. Notably, increases in tau O-GlcNAc did not alter tau phosphorylation in vivo. Using in vitro biochemical aggregation studies, we found that O-GlcNAc modification, on its own, hinders tau oligomerization. O-GlcNAc also inhibits thermally induced aggregation of an unrelated protein, TAK-1 binding protein, suggesting that a basic biochemical function of O-GlcNAc may be to p