Moderate mammalian target of rapamycin inhibition induces autophagy in HTR8/SVneo cells via O‐linked β‐N‐acetylglucosamine signaling

Zhang, Qiuxia; Na, Quan; Song, Weiwei

doi:10.1111/jog.13410

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…The HBP and mTOR pathway share sensitivities for specific macromolecules and similar responses to fluctuations in nutrition, ( 12 – 14 , 16 , 17 , 23 – 25 , 32 , 36 , 37 ), leaving a wide door for exploring possible interactions. Recent evidence has suggested that mTOR and O-GlcNAc coordinate together to direct autophagy ( 54 , 55 ). Autophagy is the process of degrading and recycling organelles, as well as other cellular components, which is significant in maintaining cellular function ( 54 ).…”

Section: Sustained O-glcnacylation Correlates With Increased Phosphormentioning

confidence: 99%

“…Treatment with mTOR inhibitors Torin1 and PP242 resulted in induced autophagy and a drop in global O-GlcNAcylation, which occurred with increased OGA and decreased OGT protein expression ( 54 ). While it appears that mTOR inhibition couples with active autophagy, another study ( 55 ) demonstrated that the acuity of mTOR suppression impacts this dynamic; moderate mTOR suppression resulted in a significant increase in autophagy, but was attenuated with severe mTOR inhibition. What's more, an inter-play between phosphorylation and O-GlcNAcylation of the autophagy regulator, Beclin1, demonstrated that moderate mTOR suppression promoted the former modification, while severe inhibition increased the latter ( 55 ).…”

Section: Sustained O-glcnacylation Correlates With Increased Phosphormentioning

confidence: 99%

“…While it appears that mTOR inhibition couples with active autophagy, another study ( 55 ) demonstrated that the acuity of mTOR suppression impacts this dynamic; moderate mTOR suppression resulted in a significant increase in autophagy, but was attenuated with severe mTOR inhibition. What's more, an inter-play between phosphorylation and O-GlcNAcylation of the autophagy regulator, Beclin1, demonstrated that moderate mTOR suppression promoted the former modification, while severe inhibition increased the latter ( 55 ). While the exact synergy between O-GlcNAc and mTOR has not been detected in autophagy, there appears to be a clear dynamic that is hinged on the spectrum of mTOR repression.…”

Section: Sustained O-glcnacylation Correlates With Increased Phosphormentioning

confidence: 99%

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Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

2018

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O-linked N-acetylglucosamine, better known as O-GlcNAc, is a sugar post-translational modification participating in a diverse range of cell functions. Disruptions in the cycling of O-GlcNAc mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, is a driving force for aberrant cell signaling in disease pathologies, such as diabetes, obesity, Alzheimer's disease, and cancer. Production of UDP-GlcNAc, the metabolic substrate for OGT, by the Hexosamine Biosynthetic Pathway (HBP) is controlled by the input of amino acids, fats, and nucleic acids, making O-GlcNAc a key nutrient-sensor for fluctuations in these macromolecules. The mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways also participate in nutrient-sensing as a means of controlling cell activity and are significant factors in a variety of pathologies. Research into the individual nutrient-sensitivities of the HBP, AMPK, and mTOR pathways has revealed a complex regulatory dynamic, where their unique responses to macromolecule levels coordinate cell behavior. Importantly, cross-talk between these pathways fine-tunes the cellular response to nutrients. Strong evidence demonstrates that AMPK negatively regulates the mTOR pathway, but O-GlcNAcylation of AMPK lowers enzymatic activity and promotes growth. On the other hand, AMPK can phosphorylate OGT leading to changes in OGT function. Complex sets of interactions between the HBP, AMPK, and mTOR pathways integrate nutritional signals to respond to changes in the environment. In particular, examining these relationships using systems biology approaches might prove a useful method of exploring the complex nature of cell signaling. Overall, understanding the complex interactions of these nutrient pathways will provide novel mechanistic information into how nutrients influence health and disease.

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Section: Sustained O-glcnacylation Correlates With Increased Phosphormentioning

confidence: 99%

Section: Sustained O-glcnacylation Correlates With Increased Phosphormentioning

confidence: 99%

Section: Sustained O-glcnacylation Correlates With Increased Phosphormentioning

confidence: 99%

See 1 more Smart Citation

Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

2018

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“…Zhang et al have reported that moderate inhibition of mTOR enhances autophagy while excessive inhibition of mTOR reduces autophagy in trophoblasts. That could be mediated by the functional loop between the O-GlcNAcylation and phosphorylation of Beclin-1 [49]. Additionally, Yang et al have reported AMPK as a negative regulator of autophagy in primary human trophoblasts [50].…”

Section: Upstream Regulators Of Autophagy For Trophoblast Cellsmentioning

confidence: 99%

Insight of Autophagy in Spontaneous Miscarriage

Qin¹,

Shen²,

Zhou³

et al. 2022

Int. J. Biol. Sci.

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In some cases of spontaneous miscarriage (SM), the exact etiology cannot be determined. Autophagy, which is responsible for cellular survival under stress conditions, has also been implicated in many diseases. Recently, it is also surmised to be correlated with SM. However, the detailed mechanism remains elusive. In fact, there are several essential steps during pregnancy establishment and maintenance: trophoblasts invasion, placentation, decidualization, enrichment and infiltration of decidua immune cells (e.g., natural killer, macrophage and T cells). Accordingly, upstream molecules and downstream effects of autophagy are discussed in these processes, respectively. Of note, autophagy regulates the crosstalk between these cells at the maternal-fetal interface as well. Aberrant autophagy is found in villi, decidual stromal cells, peripheral blood mononuclear cells in SM patients, although the findings are inconsistent among different studies. Furthermore, potential treatments targeting autophagy are included, during which rapamycin and vitamin D are hot-spots in recent literatures. To conclude, a moderately activated autophagy is deeply involved in pregnancy, suggesting that autophagy should be a regulator and promising target for treating SM.

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“…Furthermore, autophagy, a process which is governs the degradation of misfolded proteins and damaged organelles, is important for normal placental developmental activities, such as invasion and vascular remodeling of extravillous trophoblasts (EVT). Studies on HTR8/SVneo cells showed that mTOR signaling also plays a role in regulating autophagy via the modulation of Beclin1 and synaptosome associated protein 29 (SNAP29) O-GlcNAcylation (21). Enhanced autophagy levels have been observed in human and mouse placentas exposed to HIP, as well as trophoblast cells in high-glucose environments (22)(23)(24).…”

Section: Placenta Growth and Developmentmentioning

confidence: 99%

O-GlcNAcylation in Hyperglycemic Pregnancies: Impact on Placental Function

Ning

Yang

2021

Front. Endocrinol.

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The dynamic cycling of N-acetylglucosamine, termed as O-GlcNAcylation, is a post-translational modification of proteins and is involved in the regulation of fundamental cellular processes. It is controlled by two essential enzymes, O-GlcNAc transferase and O-GlcNAcase. O-GlcNAcylation serves as a modulator in placental tissue; furthermore, increased levels of protein O-GlcNAcylation have been observed in women with hyperglycemia during pregnancy, which may affect the short-and long-term development of offspring. In this review, we focus on the impact of O-GlcNAcylation on placental functions in hyperglycemia-associated pregnancies. We discuss the following topics: effect of O-GlcNAcylation on placental development and its association with hyperglycemia; maternal-fetal nutrition transport, particularly glucose transport, via the mammalian target of rapamycin and AMP-activated protein kinase pathways; and the two-sided regulatory effect of O-GlcNAcylation on inflammation. As O-GlcNAcylation in the placental tissues of pregnant women with hyperglycemia influences near- and long-term development of offspring, research in this field has significant therapeutic relevance.

show abstract

Moderate mammalian target of rapamycin inhibition induces autophagy in HTR8/SVneo cells via O‐linked β‐N‐acetylglucosamine signaling

Cited by 10 publications

References 38 publications

Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling

Insight of Autophagy in Spontaneous Miscarriage

O-GlcNAcylation in Hyperglycemic Pregnancies: Impact on Placental Function

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