PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes

Robinson, James W.; Leshchyns’ka, Iryna; Farghaian, Hovik; Hughes, William E.; Sytnyk, Vladimir; Neely, G. Gregory; Cole, Adam R.

doi:10.1042/bj20140497

Cited by 20 publications

(20 citation statements)

References 53 publications

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“…Finally, 26 PAY T NSF T 33 is recognised by Ser/Thr kinase GSK3 (Glycogen synthase kinase 3). Interestingly, it was reported that the lipid kinase phosphatidylinositol 4-kinase II α (PI4KIIα) is a substrate of GSK3 (Robinson et al 2014). This establishes a link with 19 TTR TQ L P 25 motif, described above, that is predicted phosphorylated by GSK3.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

Maaroufi

2020

Preprint

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Currently, the global COVID-19 (Coronavirus Disease-2019) pandemic is affecting the health and/or socioeconomic life of almost each people in the world. Finding vaccines and therapeutics is urgent but without forgetting to elucidate the molecular mechanisms that allow some viruses to become dangerous for humans. Here, analysis of all proteins of SARS-CoV-2 revealed a unique PPxY Late (L) domain motif 25PPAY28 in spike protein inside hot disordered loop predicted subject to phosphorylation and binding. It was demonstrated in enveloped RNA viruses that PPxY motif recruits Nedd4 E3 ubiquitin ligases and ultimately the ESCRT complex to enhance virus budding and release that means a high viral load, hence facilitating new infections. Note that PPxY motif is not present in proteins of SARS-CoV. This suggests that PPxY motif by its role in enhancing the viral load could explain why SARS-CoV-2 is more contagious than SARS-CoV. Of course, after the experimental verifications showing that PPxY motif plays the same role as reported for other enveloped RNA viruses, it could become an interesting target for the development of novel host-oriented antivirals therapeutics for preventing S protein to recruit Nedd4 E3 ubiquitin ligases partners.

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Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

Maaroufi

2020

Preprint

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“…We were surprised that knockdown of PI4KIIα had no effect on AMPA receptor-mediated synaptic transmission given previous work, using the same constructs, found a modest increase in cell surface AMPARs in cultured hippocampal neurons (Robinson et al, 2014). There are a number of possible explanations for this difference.…”

Section: Pi4kiiα and The Regulation Of Ampa Receptorsmentioning

confidence: 92%

“…Recently phosphatidylinositol 4 kinase type II α (PI4KIIα) was identified as a neuronal GSK-3β effector with a potential role in the regulation of the surface expression of AMPA receptors (Robinson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα

Amici

Lee

Pope

et al. 2019

Preprint

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Understanding the normal functions of GSK-3β in the central nervous system is of major interest because deregulation of this kinase is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. GSK-3β plays a role in the induction of NMDA receptor-dependent long-term depression (LTD) and several substrates for GSK-3β have been identified in this form of synaptic plasticity, including KLC-2, PSD-95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK-3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK-3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα had no effect on synaptic AMPA receptors but substantially inhibited synaptic NMDA receptors. Furthermore, the ability of the selective GSK-3 inhibitor, CT99021, to inhibit synaptic NMDA receptors was occluded in shRNA-PI4KIIα transfected neurons. The effects of knocking down PI4KIIα knockdown were fully rescued by a shRNAresistant wild type construct but could not be rescued by a mutant construct that was unable to be phosphorylated by GSK-3β. The data suggest that GSK-3β phosphorylates PI4KIIα to stabilize the expression of synaptic NMDA receptors.

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“…47 GSK-3a/b has been found to be involved in a wide range of cellular processes ranging from glycogen metabolism and cell growth to membrane vesicle trafficking and autophagy. 53,54 It is a critical regulator of numerous signaling pathways including the insulin and Hedgehog pathways. 47 The GSK-3a/b proteins inhibit the Wnt/b-catenin pathway via their ability to phosphorylate b-catenin.…”

Section: Discussionmentioning

confidence: 99%

6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells

et al. 2017

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PI4KIIα phosphorylation by GSK3 directs vesicular trafficking to lysosomes

Cited by 20 publications

References 53 publications

SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

SARS-CoV-2 Encodes a PPxY Late Domain Motif Known to Enhance Budding and Spread in Enveloped RNA Viruses

GSK-3β regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIα

6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells

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