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João Paulo Almeida Dos Santos, Adriana Vizuete, Fernanda Hansen, Regina Biasibetti, Carlos-Alberto Gonçalves
 O-GlcNAc transferase (OGT), an enzyme highly expressed in brain tissue, catalyzes the addition of N-acetyl-glucosamine (GlcNAc) to hydroxyl residues of serine and threonine of proteins. Brain protein O-GlcNAcylation is diminished in Alzheimer's disease (AD), and OGT targets include proteins of the insulin-signaling pathway (e.g., insulin receptor susbtrate-1, IRS-1). We hypothesized that ICV streptozotocin (STZ) also affects O-GlcNAc protein modification. We investigated hippocampal metabolic changes in Wistar rats, particularly OGT levels and insulin resistance, as well as related astroglial activities, immediately after ICV STZ administration (first week) and later on (fourth week)...
November 16, 2017: Journal of Alzheimer's Disease: JAD
Cuifang Han, Yuchao Gu, Hui Shan, Wenyi Mi, Jiahui Sun, Minghui Shi, Xinling Zhang, Xinzhi Lu, Feng Han, Qianhong Gong, Wengong Yu
SIRT1 is the most evolutionarily conserved mammalian sirtuin, and it plays a vital role in the regulation of metabolism, stress responses, genome stability, and ageing. As a stress sensor, SIRT1 deacetylase activity is significantly increased during stresses, but the molecular mechanisms are not yet fully clear. Here, we show that SIRT1 is dynamically modified with O-GlcNAc at Ser 549 in its carboxy-terminal region, which directly increases its deacetylase activity both in vitro and in vivo. The O-GlcNAcylation of SIRT1 is elevated during genotoxic, oxidative, and metabolic stress stimuli in cellular and mouse models, thereby increasing SIRT1 deacetylase activity and protecting cells from stress-induced apoptosis...
November 14, 2017: Nature Communications
Gloria M Trinca, Christy R Hagan
O-GlcNAcylation is emerging as a critical regulatory post-translational modification, impacting proteins that regulate cell division, apoptosis, metabolism, cell signaling, and transcription. O-GlcNAc also affects biological homeostasis by integrating information coming from the environment, such as nutrient conditions and extracellular stimuli, with cellular response. Aberrant O-GlcNAc modulation has been linked to metabolic and neurodegenerative diseases, as well as cancers. While many studies have highlighted the significance of O-GlcNAc in cancer, a specific function for O-GlcNAc during tumorigenesis remains unclear and seems to differ according to cancer type...
November 10, 2017: Journal of Bioenergetics and Biomembranes
Aime Lopez Aguilar, Yu Gao, Xiaomeng Hou, Gregoire Lauvau, John R Yates, Peng Wu
During an acute infection, antigenic stimulation leads to activation, expansion, and differentiation of naïve CD8(+) T cells, first into cytotoxic effector cells and eventually into long-lived memory cells. T cell antigen receptors (TCRs) detect antigens on antigen-presenting cells (APCs) in the form of antigenic peptides bound to major histocompatibility complex I (MHC-I)-encoded molecules and initiate TCR signal transduction network. This process is mediated by phosphorylation of many intracellular signaling proteins...
November 10, 2017: ACS Chemical Biology
Kim B Pælestik, Nichlas R Jespersen, Rebekka V Jensen, Jacob Johnsen, Hans Erik Bøtker, Steen B Kristiansen
BACKGROUND: Hypoglycemia is associated with increased mortality rate in patients with diabetes. The underlying mechanisms may involve reduced myocardial tolerance to ischemia and reperfusion (IR) or reduced capacity for ischemic preconditioning (IPC). As IPC is associated with increased myocardial glucose uptake (MGU) during reperfusion, cardioprotection is linked to glucose metabolism possibly by O-linked β-N-acetylglucosamine (O-GlcNAc). We aimed to investigate the impact of hypoglycemia in hearts from animals with diabetes on myocardial IR tolerance, on the efficacy of IPC and whether modulations of MGU and O-GlcNAc levels are involved in the underlying mechanisms...
November 9, 2017: Cardiovascular Diabetology
Juan Hu, Yueying Li, Ying Li, Bo Tang, Chun-Yang Zhang
Protein glycosylation is a ubiquitous post-translational modification that plays crucial roles in modulating biological recognition events in development and physiology. Human O-GlcNAc transferase (OGT) is an intracellular enzyme responsible for O-linked N-acetylglucosamine (O-GlcNAc) glycosylation, and the deregulation of OGT activity occurs in cancer, diabetes, and neurodegenerative disease. Here we develop a single quantum dot (QD)-based nanosensor for sensitive OGT assay. We design a Cy5/biotin-modified peptide with a serine hydroxyl group for sensing OGT and a protease site adjacent to the glycosylation site for proteinase cleavage, with a universal nonradioactive UDP-GlcNAc as the sugar donor and a Cy5/biotin-modified peptide as the substrate...
November 17, 2017: Analytical Chemistry
Changmin Peng, Yue Zhu, Wanjun Zhang, Qinchao Liao, Yali Chen, Xinyuan Zhao, Qiang Guo, Pan Shen, Bei Zhen, Xiaohong Qian, Dong Yang, Jin-San Zhang, Dongguang Xiao, Weijie Qin, Huadong Pei
The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity...
November 2, 2017: Molecular Cell
Heather J Tarbet, Clifford A Toleman, Michael Boyce
O-linked β-N-acetylglucosamine (O-GlcNAc) is a critical post-translational modification (PTM) of thousands of intracellular proteins. Reversible O-GlcNAcylation governs many aspects of cell physiology and is dysregulated in numerous human diseases. Despite this broad pathophysiological significance, major aspects of O-GlcNAc signaling remain poorly understood, including the biochemical mechanisms through which O-GlcNAc transduces information. Recent work from many labs, including our own, has revealed that O-GlcNAc, like other intracellular PTMs, can control its substrates' functions by inhibiting or inducing protein-protein interactions...
November 3, 2017: Biochemistry
V L Sodi, Z A Bacigalupa, C M Ferrer, J V Lee, W A Gocal, D Mukhopadhyay, K E Wellen, M Ivan, M J Reginato
Elevated O-GlcNAcylation is associated with disease states such as diabetes and cancer. O-GlcNAc transferase (OGT) is elevated in multiple cancers and inhibition of this enzyme genetically or pharmacologically inhibits oncogenesis. Here we show that O-GlcNAcylation modulates lipid metabolism in cancer cells. OGT regulates expression of the master lipid regulator the transcription factor sterol regulatory element binding protein 1 (SREBP-1) and its transcriptional targets both in cancer and lipogenic tissue...
October 23, 2017: Oncogene
Chia-Wei Hu, Matthew Worth, Dacheng Fan, Baobin Li, Hao Li, Lei Lu, Xiaofang Zhong, Ziqing Lin, Liming Wei, Ying Ge, Lingjun Li, Jiaoyang Jiang
O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential human glycosyltransferase that adds O-GlcNAc modifications to numerous proteins. However, little is known about the mechanism with which OGT recognizes various protein substrates. Here we report on GlcNAc electrophilic probes (GEPs) to expedite the characterization of OGT-substrate recognition. Data from mass spectrometry, X-ray crystallization, and biochemical and radiolabeled kinetic assays support the application of GEPs to rapidly report the impacts of OGT mutations on protein substrate or sugar binding and to discover OGT residues crucial for protein recognition...
October 23, 2017: Nature Chemical Biology
Ilhan Akan, Stephanie Olivier-Van Stichelen, Michelle R Bond, John A Hanover
Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient sensitive nucleocytoplasmic posttranslational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. The O-GlcNAc modification is highly abundant in the mammalian brain, and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's...
October 19, 2017: Journal of Neurochemistry
Aime Lopez Aguilar, Xiaomeng Hou, Liuqing Wen, Peng George Wang, Peng Wu
Modification of nuclear and cytoplasmic proteins by the addition or removal of O-GlcNAc dynamically impacts multiple biological processes. Here we present the development of a chemoenzymatic histology method for the detection of O-GlcNAc in tissue samples. We applied this method to screen murine organs, uncovering specific O-GlcNAc distribution patterns in different tissue structures. We then utilized our histology method for O-GlcNAc detection in human brain samples from healthy donors and donors with Alzheimer's disease and found higher levels of O-GlcNAc in samples from healthy donors...
October 17, 2017: Chembiochem: a European Journal of Chemical Biology
Yoon Sook Kim, Minjun Kim, Mee Young Choi, Dong Hoon Lee, Gu Seob Roh, Hyun Joon Kim, Sang Soo Kang, Gyeong Jae Cho, Ki Hun Park, Seong-Jae Kim, Ji-Myong Yoo, Wan Sung Choi
Aralia elata (Miq) Seem (AES) is a medicinal plant used in traditional Chinese and Korean medicine for the treatment of several diseases, including diabetes. This study aimed to investigate the neuroprotective effect of AES extract against high glucose-induced retinal injury in diabetic mice. AES extract (20 and 100 mg/kg body weight) was orally administered to control mice or mice with streptozotocin-induced diabetes. Protein levels of O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT), carbohydrate-responsive element-binding protein (ChREBP), sterol regulatory element-binding protein (SREBP)-1, thioredoxin-interacting protein (TXNIP), fatty acid synthase (FAS), and acetyl CoA carboxylase (ACC) were analyzed by western blotting...
October 2017: Journal of Medicinal Food
Hiroki Tsumoto, Yoshihiro Akimoto, Tamao Endo, Yuri Miura
Protein O-GlcNAcylation regulates various biological processes, and is associated with several diseases. Therefore, the development of quantitative proteomics is important for understanding the mechanisms of O-GlcNAc-related diseases. We previously reported selective enrichment of O-GlcNAcylated peptides, which provided high-selectivity and effective release by a novel thiol-alkyne and thiol-disulfide exchange. Here, we describe a new approach using initial isobaric tag labeling for relative quantification followed by enrichment and β-elimination/Michael addition with dithiothreitol for identification of both proteins and modification sites...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
Zhe Li, Xueyan Li, Shanshan Nai, Qizhi Geng, Ji Liao, Xingzhi Xu, Jing Li
Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as previously reported...
October 11, 2017: Journal of Biological Chemistry
Weina Liu, Hongmei Wang, Xiangli Xue, Jie Xia, Jiatong Liu, Zhengtang Qi, Liu Ji
BACKGROUND: Prenatal exposure to glucocorticoids (GCs) has been found to trigger abnormal behaviors and deleterious neurological effects on offspring both in animals and in humans. The sex differences in depression have been replicated in numerous studies across cultures, persisting throughout the reproductive years. As an X-linked gene in rodents and in humans, O-GlcNAc transferase (OGT) may provide a novel perspective for the sex differences in depression. METHODS: In the last third of pregnancy (gestational day 14-21), rats were subcutaneously administered either 0...
September 29, 2017: Journal of Affective Disorders
Emi Ishimura, Takatoshi Nakagawa, Kazumasa Moriwaki, Seiichi Hirano, Yoshinobu Matsumori, Michio Asahi
Increasing incidence of various cancers has been reported in diabetic patients. O-linked N-acetylglucosamine (O-GlcNAc) modification of proteins at serine/threonine residues (O-GlcNAcylation) is an essential post-translational modification that is upregulated in diabetic patients and has been implicated in tumor growth. However, the mechanisms by which O-GlcNAcylation promotes tumor growth remain unclear. Given that AMP-activated kinase (AMPK) has been thought to play important roles in suppressing tumor growth, we evaluated the involvement of AMPK O-GlcNAcylation on the growth of LoVo cells, a human colon cancer cell line...
October 3, 2017: Cancer Science
Yubo Liu, Yang Ren, Yu Cao, Huang Huang, Qiong Wu, Wenli Li, Sijin Wu, Jianing Zhang
O-GlcNAc transferase (OGT) plays an important role in regulating numerous cellular processes through reversible post-translational modification of nuclear and cytoplasmic proteins. However, the function of O-GlcNAcylation is still not well understood. Cell permeable OGT inhibitors are needed to manipulate O-GlcNAcylation levels and clarify the regulatory mechanism of this modification. Here, we report a specific natural-product OGT inhibitor (L01), which was identified from a structure-based virtual screening analysis...
September 26, 2017: Scientific Reports
Baobin Li, Hao Li, Chia-Wei Hu, Jiaoyang Jiang
The O-linked β-N-acetyl glucosamine (O-GlcNAc) modification dynamically regulates the functions of numerous proteins. A single human enzyme O-linked β-N-acetyl glucosaminase (O-GlcNAcase or OGA) hydrolyzes this modification. To date, it remains largely unknown how OGA recognizes various substrates. Here we report the structures of OGA in complex with each of four distinct glycopeptide substrates that contain a single O-GlcNAc modification on a serine or threonine residue. Intriguingly, these glycopeptides bind in a bidirectional yet conserved conformation within the substrate-binding cleft of OGA...
September 22, 2017: Nature Communications
Gloria M Trinca, Merit L Goodman, Evangelia K Papachristou, Clive S D'Santos, Prabhakar Chalise, Rashna Madan, Chad Slawson, Christy R Hagan
Emerging clinical trial data implicate progestins in the development of breast cancer. While the role for the progesterone receptor (PR) in this process remains controversial, it is clear that PR, a steroid-activated nuclear receptor, alters the transcriptional landscape of breast cancer. PR interacts with many different types of proteins, including transcriptional co-activators and co-repressors, transcription factors, nuclear receptors, and proteins that post-translationally modify PR (i.e., kinases and phosphatases)...
September 19, 2017: Hormones & Cancer
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