O-GlcNAcylation Regulates Primary Ciliary Length by Promoting Microtubule Disassembly

Tian, Jie; Qin, Hongmin

doi:10.1016/j.isci.2019.01.031

Cited by 22 publications

(19 citation statements)

References 59 publications

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“…First, primary ciliary length negatively correlates with the cellular OGN levels both in hTERT-RPE1 and IMCD3 cells. Molecular mechanistic studies showed that OGN of α-tubulin and histone deacetylase 6 (HDAC6) are involved in ciliary shortening through promotion of axonemal microtubule disassembly [51]. Consistent with the work of Yu et al, primary cilia were fewer and shorter in the diabetic mouse eyes, trachea, and skin cells compared to those of wild type, and increased OGN of RPE1 cells in culture impaired ciliogenesis [52].…”

Section: The Nutrient Sensor O-glcnac Contributes To Primary Ciliary supporting

confidence: 55%

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Tian

Gomeshtapeh

2020

Biomolecules

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The primary cilium, an antenna-like structure on most eukaryotic cells, functions in transducing extracellular signals into intracellular responses via the receptors and ion channels distributed along it membrane. Dysfunction of this organelle causes an array of human diseases, known as ciliopathies, that often feature obesity and diabetes; this indicates the primary cilia’s active role in energy metabolism, which it controls mainly through hypothalamic neurons, preadipocytes, and pancreatic β-cells. The nutrient sensor, O-GlcNAc, is widely involved in the regulation of energy homeostasis. Not only does O-GlcNAc regulate ciliary length, but it also modifies many components of cilia-mediated metabolic signaling pathways. Therefore, it is likely that O-GlcNAcylation (OGN) plays an important role in regulating energy homeostasis in primary cilia. Abnormal OGN, as seen in cases of obesity and diabetes, may play an important role in primary cilia dysfunction mediated by these pathologies.

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Section: The Nutrient Sensor O-glcnac Contributes To Primary Ciliary supporting

confidence: 55%

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Tian

Gomeshtapeh

2020

Biomolecules

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“…Although we need to take the alloxan result with a bit of caution (Alloxan is not a specific OGT inhibitor), Tian et al. also discovered a negative effect on cilia by O-GlcNAc ( 23 ), congruent with the results from Yu et al. ( 22 ).…”

Section: O-glcnac Negatively Regulates Cilia In Quiescent Cellssupporting

confidence: 54%

“…Two papers came out in 2018 and 2019, describing that O-GlcNAc exerts a negative effect on ciliogenesis and cilia lengths ( 22 , 23 ). Yu et al ( 22 ) first utilized DB mice that harbor diabetic mutations in the leptin receptor, and noticed that DB mice have fewer and shorter cilia than wild type.…”

Section: O-glcnac Negatively Regulates Cilia In Quiescent Cellsmentioning

confidence: 99%

Centrosomes: Til O-GlcNAc Do Us Apart

Yuan

Tang

2021

Front. Endocrinol.

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The centrosome apparatus is vital for spindle assembly and chromosome segregation during mitotic divisions. Its replication, disjunction and separation have to be fine-tuned in space and time. A multitude of post-translational modifications (PTMs) have been implicated in centrosome modulation, including phosphorylation, ubiquitination and acetylation. Among them is the emerging O-linked N-acetylglucosamine (O-GlcNAc) modification. This quintessential PTM has a sole writer, O-GlcNAc transferase (OGT), and the only eraser, O-GlcNAcase (OGA). O-GlcNAc couples glucose metabolism with signal transduction and forms a yin-yang relationship with phosphorylation. Evidence from proteomic studies as well as single protein investigations has pinpointed a role of O-GlcNAc in centrosome number and separation, centriole number and distribution, as well as the cilia machinery emanating from the centrosomes. Herein we review our current understanding of the sweet modification embedded in centrosome dynamics and speculate that more molecular details will be unveiled in the future.

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“…A decrease in O-GlcNAcylation levels elevates autophagic flux by promoting the fusion of autophagosomes and lysosomes [ 6 , 25 ]. In the present study, we utilized small molecule inhibitors of OGT, alloxan [ 27 , 28 ], BZX2 [ 29 ], and OSMI-1 [ 30 ], and determined whether and how a decrease in O-GlcNAcylation contributes to autophagy in neurons. Collectively, our findings suggest that the inhibition of O-GlcNAcylation modification stimulates LC3-II expression and suppresses the autophagic substrate p62/SQSTM1 through the mTOR-dependent pathway, thereby revealing an important association between autophagy and O-GlcNAcylation in cortical neurons.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons

et al. 2020

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O-GlcNAc transferase (OGT) is a ubiquitous enzyme that regulates the addition of β-N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of target proteins. Autophagy is a cellular process of self-digestion, in which cytoplasmic resources, such as aggregate proteins, toxic compounds, damaged organelles, mitochondria, and lipid molecules, are degraded and recycled. Here, we examined how three different OGT inhibitors, alloxan, BXZ2, and OSMI-1, modulate O-GlcNAcylation in rat cortical neurons, and their autophagic effects were determined by immunoblot and immunofluorescence assays. We found that the treatment of cortical neurons with an OGT inhibitor decreased O-GlcNAcylation levels and increased LC3-II expression. Interestingly, the pre-treatment with rapamycin, an mTOR inhibitor, further increased the expression levels of LC3-II induced by OGT inhibition, implicating the involvement of mTOR signaling in O-GlcNAcylation-dependent autophagy. In contrast, OGT inhibitor-mediated autophagy was significantly attenuated by 3-methyladenine (3-MA), a blocker of autophagosome formation. However, when pre-treated with chloroquine (CQ), a lysosomotropic agent and a late-stage autophagy inhibitor, OGT inhibitors significantly increased LC3-II levels along with LC3 puncta formation, indicating the stimulation of autophagic flux. Lastly, we found that OGT inhibitors significantly decreased the levels of the autophagy substrate p62/SQSTM1 while increasing the expression of lysosome-associated membrane protein 1 (LAMP1). Together, our study reveals that the modulation of O-GlcNAcylation by OGT inhibition regulates mTOR-dependent autophagy in rat cortical neurons.

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O-GlcNAcylation Regulates Primary Ciliary Length by Promoting Microtubule Disassembly

Cited by 22 publications

References 59 publications

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism

Centrosomes: Til O-GlcNAc Do Us Apart

Pharmacological Inhibition of O-GlcNAc Transferase Promotes mTOR-Dependent Autophagy in Rat Cortical Neurons

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