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Jo S, Esch N, Nguyen A, Wong A, Mohan R, Kim C, Blandino-Rosano M, Bernal-Mizrachi E, Alejandro EU. Loss of O-GlcNAcylation modulates mTORC1 and autophagy in β cells, driving diabetes 2 progression. JCI insight 2024 9(23) 39388284
Abstract:
Type 2 diabetes (T2D) arises when pancreatic β cells fail to produce sufficient insulin to control blood glucose appropriately. Aberrant nutrient sensing by O-GlcNAcylation and mTORC1 is linked to T2D and the failure of insulin-producing β cells. However, the nature of their crosstalk in β cells remains unexplored. Recently, O-GlcNAcylation, a posttranslation modification controlled by enzymes O-GlcNAc transferase/O-GlcNAcase (OGT/OGA), emerged as a pivotal regulator for β cell health; deficiency in either enzyme causes β cell failure. The present study investigates the previously unidentified connection between nutrient sensor OGT and mTORC1 crosstalk to regulate β cell mass and function in vivo. We show reduced OGT and mTORC1 activity in islets of a preclinical β cell dysfunction model and islets from humans with obesity. Using loss or gain of function of OGT, we identified that O-GlcNAcylation positively regulated mTORC1 signaling in β cells. O-GlcNAcylation negatively modulated autophagy, as the removal of OGT increased autophagy, while the deletion of OGA decreased it. Increasing mTORC1 signaling, via deletion of TSC2, alleviated the diabetic phenotypes by increasing β cell mass but not β cell function in OGT-deficient mice. Downstream phospho-protein signaling analyses revealed diverging effects on MKK4 and calmodulin signaling between islets with OGT, TSC2, or combined deletion. These data provide evidence of OGT's significance as an upstream regulator of mTORC1 and autophagy, crucial for the regulation of β cell function and glucose homeostasis.
O-GlcNAc proteins:
MTOR, RPTOR, RPTOR, LST8, LST8, MTOR
Species: Homo sapiens, Mus musculus
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Cho HI, Jo S, Kim MS, Kim HB, Liu X, Xuan Y, Cho JW, Jang YK. SETD5 regulates the OGT-catalyzed O-GlcNAcylation of RNA polymerase II, which is involved in the stemness of colorectal cancer cells. Scientific reports 2023 13(1) 37963940
Abstract:
The dosage-dependent recruitment of RNA polymerase II (Pol II) at the promoters of genes related to neurodevelopment and stem cell maintenance is required for transcription by the fine-tuned expression of SET-domain-containing protein 5 (SETD5). Pol II O-GlcNAcylation by O-GlcNAc transferase (OGT) is critical for preinitiation complex formation and transcription cycling. SETD5 dysregulation has been linked to stem cell-like properties in some cancer types; however, the role of SETD5 in cancer cell stemness has not yet been determined. We here show that aberrant SETD5 overexpression induces stemness in colorectal cancer (CRC) cells. SETD5 overexpression causes the upregulation of PI3K-AKT pathway-related genes and cancer stem cell (CSC) markers such as CD133, Kruppel-like factor 4 (KLF4), and estrogen-related receptor beta (ESRRB), leading to the gain of stem cell-like phenotypes. Our findings also revealed a functional relationship between SETD5, OGT, and Pol II. OGT-catalyzed Pol II glycosylation depends on SETD5, and the SETD5-Pol II interaction weakens in OGT-depleted cells, suggesting a SETD5-OGT-Pol II interdependence. SETD5 deficiency reduces Pol II occupancy at PI3K-AKT pathway-related genes and CD133 promoters, suggesting a role for SETD5-mediated Pol II recruitment in gene regulation. Moreover, the SETD5 depletion nullified the SETD5-induced stemness of CRC cells and Pol II O-GlcNAcylation. These findings support the hypothesis that SETD5 mediates OGT-catalyzed O-GlcNAcylation of RNA Pol II, which is involved in cancer cell stemness gain via CSC marker gene upregulation.
O-GlcNAc proteins:
SETD5
Species: Homo sapiens
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Lockridge A, Jo S, Gustafson E, Damberg N, Mohan R, Olson M, Abrahante JE, Alejandro EU. Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2. Cell reports 2020 31(5) 32375037
Abstract:
During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca2+ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.
O-GlcNAc proteins:
AT2A2, AT2A2
Species: Homo sapiens, Mus musculus
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Jo S, Lockridge A, Alejandro EU. eIF4G1 and carboxypeptidase E axis dysregulation in O-GlcNAc transferase-deficient pancreatic β-cells contributes to hyperproinsulinemia in mice. The Journal of biological chemistry 2019 294(35) 31300553
Abstract:
An early hallmark of type 2 diabetes is a failure of proinsulin-to-insulin processing in pancreatic β-cells, resulting in hyperproinsulinemia. Proinsulin processing is quite sensitive to nutrient flux, and β-cell-specific deletion of the nutrient-sensing protein modifier OGlcNAc transferase (βOGTKO) causes β-cell failure and diabetes, including early development of hyperproinsulinemia. The mechanisms underlying this latter defect are unknown. Here, using several approaches, including site-directed mutagenesis, Click O-GlcNAc labeling, immunoblotting, and immunofluorescence and EM imaging, we provide the first evidence for a relationship between the O-GlcNAcylation of eukaryotic translation initiation factor 4γ1 (eIF4G1) and carboxypeptidase E (CPE)-dependent proinsulin processing in βOGTKO mice. We first established that βOGTKO hyperproinsulinemia is independent of age, sex, glucose levels, and endoplasmic reticulum-CCAAT enhancer-binding protein homologous protein (CHOP)-mediated stress status. Of note, OGT loss was associated with a reduction in β-cell-resident CPE, and genetic reconstitution of CPE in βOGTKO islets rescued the dysfunctional proinsulin-to-insulin ratio. We show that although CPE is not directly OGlcNAc modified in islets, overexpression of the suspected OGT target eIF4G1, previously shown to regulate CPE translation in β-cells, increases islet CPE levels, and fully reverses βOGTKO islet-induced hyperproinsulinemia. Furthermore, our results reveal that OGT O-GlcNAc-modifies eIF4G1 at Ser-61 and that this modification is critical for eIF4G1 protein stability. Together, these results indicate a direct link between nutrient-sensitive OGT and insulin processing, underscoring the importance of post-translational O-GlcNAc modification in general cell physiology.
O-GlcNAc proteins:
IF4G1
Species: Homo sapiens
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