O-GlcNAc transferase modulates the cellular endocytosis machinery by controlling the formation of clathrin-coated pits

Rahmani, Sadia; Ahmed, Hafsa; Ibazebo, Osemudiamen; Fussner-Dupas, Eden; Wakarchuk, Warren W.; Antonescu, Costin N.

doi:10.1016/j.jbc.2023.102963

Cited by 4 publications

(6 citation statements)

References 78 publications

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“…This was performed as previously described 78 . After treatments as indicated, cells were washed with ice-cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Control of GSK3β nuclear localization by amino acid signaling requires GATOR1 but is mTORC1-independent

Schwendener Forkel,

Ibazebo,

Soha

et al. 2024

Preprint

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The availability of certain amino acids regulates cell survival, proliferation, growth, differentiation, and other cellular functions. Sensing of amino acids that converges on the GATOR1 and GATOR2 complexes supports activation of mTORC1 during amino acid replete conditions. Whether amino acid-derived cues regulate additional pathways remains poorly understood. We uncover that amino acid sensing involving GATOR1 and GATOR2 regulates the cellular localization of glycogen synthase kinase 3beta (GSK3beta). GATOR1 is required to recruit a subset of GSK3beta to the lysosome selectively in the presence of amino acids. In addition, while under nutrient replete conditions GSK3beta is largely cytosolic, amino acid starvation drives a portion of GSK3beta into the nucleus. Acute replenishment of specific amino acids in starved cells triggered nuclear exit of GSK3beta. This amino acid-stimulated GSK3beta nuclear exit required GATOR1 and GATOR2 but was independent of mTORC1 and its activating RagA/B GTPases. This suggests that GATOR1 has a function that diverges from control of mTORC1 to regulate the nucleocytoplasmic shuttling of GSK3beta. Furthermore, experimental restriction of GSK3beta to the cytoplasm decreased cell survival in amino acid deficient conditions. This suggests that control of GSK3beta nuclear localization by GATOR-dependent signals represents a cellular adaptation to metabolic stress that supports cell survival.

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“…This was performed as previously described 78 . After treatments as indicated, cells were washed with ice-cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Control of GSK3β nuclear localization by amino acid signaling requires GATOR1 but is mTORC1-independent

Schwendener Forkel,

Ibazebo,

Soha

et al. 2024

Preprint

Self Cite

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“…A decrease in O-GlcNAc levels induced by glucose deprivation has similar effects on CCPs. Conversely, an increase in O-GlcNAc levels by Thiamet G treatment slightly reduces the recruitment of clathrin to CCPs and the fraction of short time-life CCPs [104] (Figure 4). Interestingly, O-GlcNAc cycling can differentially regulate the recruitment of EAPs that are required for CCP initiation and stabilization [23,105].…”

Section: Clathrin-coated Pits Formation and Transmembrane Receptors E...mentioning

confidence: 99%

“…Interestingly, O-GlcNAc cycling can differentially regulate the recruitment of EAPs that are required for CCP initiation and stabilization [23,105]. Loss of OGT increases the recruitment of CALM but decreases the recruitment of Epsin 1 to CCPs [104] (Figure 4). O-GlcNAc sites have been identified on CALM and Epsin 1 (Table 2), but further experiments are needed to determine whether their recruitment to CCPs is regulated by their own O-GlcNAc status.…”

Section: Clathrin-coated Pits Formation and Transmembrane Receptors E...mentioning

confidence: 99%

“…The mutation of the mapped and putative O-GlcNAc sites on AAK1 (T360, T448, and T441, S447, T507, S519 and S650) enhances the colocalization of AAK1 with clathrin, suggesting that O-GlcNAcylation of AAK1 could negatively regulate the recruitment of the kinase to CCPs (Figure 4). Interestingly, the activity of AAK1 is required to increase CCPs initiation when OGT is silenced, but whether the O-GlcNAcylation of AAK1 inhibits its kinase activity remains to be confirmed [104]. Furthermore, phosphorylation of AP2µ2 by AAK1 stabilizes the open conformation of AP2 and its subsequent membrane binding [106].…”

Section: Clathrin-coated Pits Formation and Transmembrane Receptors E...mentioning

confidence: 99%

“…AP2 can directly interact with transmembrane receptors that need to be internalized, notably via the binding of µ2 subunit with specific motifs in the cytoplasmic domain of cargo [107]. In that respect, modulating the recruitment of AAK1 to CCPs by O-GlcNAc cycling could regulate the rate of receptors internalization, as shown for the EGF (EGFR) and transferrin (TfR) receptors [104]. Upon OGT silencing in human retinal pigment epithelial cells, EGFR is proportionally increased in the larger clathrin-labeled structures observed at the cell surface, but TfR recruitment is less effective [104].…”

Section: Clathrin-coated Pits Formation and Transmembrane Receptors E...mentioning

confidence: 99%

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O-GlcNAc Dynamics: The Sweet Side of Protein Trafficking Regulation in Mammalian Cells

Ahmed

Lemaire

Scache

et al. 2023

Cells

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The transport of proteins between the different cellular compartments and the cell surface is governed by the secretory pathway. Alternatively, unconventional secretion pathways have been described in mammalian cells, especially through multivesicular bodies and exosomes. These highly sophisticated biological processes rely on a wide variety of signaling and regulatory proteins that act sequentially and in a well-orchestrated manner to ensure the proper delivery of cargoes to their final destination. By modifying numerous proteins involved in the regulation of vesicular trafficking, post-translational modifications (PTMs) participate in the tight regulation of cargo transport in response to extracellular stimuli such as nutrient availability and stress. Among the PTMs, O-GlcNAcylation is the reversible addition of a single N-acetylglucosamine monosaccharide (GlcNAc) on serine or threonine residues of cytosolic, nuclear, and mitochondrial proteins. O-GlcNAc cycling is mediated by a single couple of enzymes: the O-GlcNAc transferase (OGT) which catalyzes the addition of O-GlcNAc onto proteins, and the O-GlcNAcase (OGA) which hydrolyses it. Here, we review the current knowledge on the emerging role of O-GlcNAc modification in the regulation of protein trafficking in mammalian cells, in classical and unconventional secretory pathways.

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Cargo-selective regulation of clathrin-mediated endocytosis by AMP-activated protein kinase

Orofiamma,

Delos Santos,

Mehrabi

et al. 2024

Preprint

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The cell surface abundance of many proteins is controlled by clathrin-mediated endocytosis (CME). CME is driven by the assembly of clathrin and other proteins on the inner leaflet of the plasma membrane into clathrin-coated pits (CCPs). Regulation of CCP dynamics allows for control of the function of specific cell surface proteins, impacting a range of cellular outcomes. AMP-activated protein kinase (AMPK) becomes activated upon metabolic insufficiency and facilitates cellular adaptation to nutrient stress. Here, we examined how AMPK regulates CME and the cell surface membrane traffic of β1-integrin. We find that AMPK controls CCP dynamics and regulates the abundance of the endocytic adaptor protein Dab2 within CCPs in a manner that requires the GTPase Arf6, thus selectively promoting the CCP recruitment and internalization of β1-integrin. This reveals a novel signaling pathway for cargo-selective metabolic regulation of CME by AMPK, impacting the function of cell surface proteins such as integrins.

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O-GlcNAc transferase modulates the cellular endocytosis machinery by controlling the formation of clathrin-coated pits

Cited by 4 publications

References 78 publications

Control of GSK3β nuclear localization by amino acid signaling requires GATOR1 but is mTORC1-independent

Control of GSK3β nuclear localization by amino acid signaling requires GATOR1 but is mTORC1-independent

O-GlcNAc Dynamics: The Sweet Side of Protein Trafficking Regulation in Mammalian Cells

Cargo-selective regulation of clathrin-mediated endocytosis by AMP-activated protein kinase

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