Regulation of PI4P levels by PI4KIIIα during G-protein-coupled PLC signaling in <i>Drosophila</i> photoreceptors

Balakrishnan, Sruthi; Basu, Urbashi; Shinde, Dhananjay; Thakur, Rajan; Jaiswal, Manish; Raghu, Padinjat

doi:10.1242/jcs.217257

Cited by 28 publications

(32 citation statements)

References 37 publications

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“…Instead, the Stt4 PI4K complex I may generate the inducible PI4P signal in mother cells. In support of our results, a recent study has implicated PI4K complex I in stimulus-induced PI(4,5)P 2 synthesis in metazoan cells (Balakrishnan et al, 2018).…”

Section: Pi4p Metabolism Controls Its Distributionsupporting

confidence: 92%

A Cytoplasmic GOLD Protein Controls Cell Polarity

Omnus

Cadou

et al. 2018

Preprint

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Phosphoinositide lipids provide spatial landmarks during polarized secretion.Here, we elucidate a role for phosphatidylinositol 4-phosphate (PI4P) metabolism in the control of cell polarity. In budding yeast, PI4P is enriched at the plasma membrane of growing daughter cells. Upon heat shock however, PI4P rapidly increases at the plasma membrane in mother cells resulting in a more uniform PI4P distribution. Rather than phosphoinositide kinase activation, PI4P hydrolysis is impaired to generate the heat-induced PI4P signal in mother cells. This fine tune control of PI4P metabolism is mediated through attenuation of the Osh3 protein that binds and presents PI4P to a phosphoinositide phosphatase.

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Section: Pi4p Metabolism Controls Its Distributionsupporting

confidence: 92%

A Cytoplasmic GOLD Protein Controls Cell Polarity

Omnus

Cadou

et al. 2018

Preprint

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“…PI4KA encodes the lipid kinase PI4KIIIα, which is involved in synthesizing the phosphoinositide, phosphatidylinositol 4,5-biphosphate (PI(4,5)P2), that recruits and regulates PM proteins and thereby governs diverse cellular processes including vesicular trafficking, ion transport, and actin cytoskeletal dynamics (58). PI4KA depletion was found to disrupt localization of PI(4,5)P2-associated proteins, reduce cellular responses to external stimuli (59,60), and impair synapse maintenance (61). Our prioritization of PI4KA in contributing to SCZ and ASD risk is consistent with prior associations of PI4KA polymorphisms in SCZ (62)(63)(64) and with growing evidence that PI4KA may play an important role in synaptic function.…”

Section: Discussionmentioning

confidence: 99%

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Forsyth

Nachun

Gandal

et al. 2019

Preprint

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Word Count: 244 Main Text Word Count: 4761 Number of Figures: 7 Number of Tables: 2Supplements: 1 supplementary information file + 1 excel file containing 2 supplementary data tables Abstract Background: 22q11.2 copy number variants (CNVs) are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear.Methods: Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and pathophysiological signatures of SCZ and ASD to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder.Results: Polygenic risk for SCZ and ASD converged on partially overlapping gene networks involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for networks involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network that disproportionately affected SCZ-and ASD-associated neurodevelopmental networks, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. Conclusions:The current approach provides a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.(M4,M6,M7,M12,M13,M15). M1 was consistently enriched for ASD risk variants, but not for down-regulated genes in ASD cortex. However, M1 was highly enriched for genes expressed specifically during fetal development, suggesting that this likely reflects a floor effect in postnatal expression of these genes. Down-regulated genes in ASD and SCZ cortextherefore appear to at least partially reflect direct effects of genetic risk, and we focused on 22qBD-PPI network overlap with down-regulated genes for subsequent analyses.Given the size of the 22qBD-PPI network and each DGE gene-set, the 22qBD-PPI network was significantly enriched for down-regulated genes in both SCZ (~11% of the 22qBD-PPI network; p=0.006) and ASD (~14% of the 22qBD-PPI network;p=2.0x10 -4 ). Additionally, compared to all regions of the genome (i.e., Genomic-RegionBD-PPI networks), the 22qBD-PPI network was in the ~93 rd and ~96 th percentiles for overlap with down-regulated genes in SCZ and ASD, respectively ( Fig. 6B; Table S4). Compared to the connectivity of random sets of 38 seed genes (i.e...

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“…This method detects and allows quantification of a signature parent-daughter ion pair for a given molecule with high sensitivity [24]. Fragmentation of any PIP and PIP 2 parent ions results in a loss of a neutral head group of fixed masses of 382 and 490 Da respectively [25]. When 18 O-ATP is used in this kinase reaction, both the mass of the parent PIP, product and consequently, the neutral fragment generated due to fragmentation, increases by 6 Da to 496 Da (Figure 1B indicates the 18 O in red).…”

Section: Resultsmentioning

confidence: 99%

A novel mass assay to measure phosphatidylinositol-5-phosphate from cells and tissues

Ghosh

Sharma

Shinde

et al. 2019

Preprint

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Phosphatidylinositol-5-phosphate (PI5P) is a low abundance lipid proposed to have functions in cell migration, DNA damage responses, receptor trafficking and insulin signalling in metazoans. However, studies of PI5P function are limited by the lack of scalable techniques to quantify its level from cells and tissues in multicellular organisms. Currently, PI5P measurement requires the use of radionuclide labelling approaches that are not easily applicable in tissues or in vivo samples. In this study, we describe a simple and reliable, non-radioactive mass assay to measure total PI5P levels from cells and tissues of Drosophila, a genetically tractable multicellular model. We use 18O-ATP to label PI5P from tissue extracts while converting it into PI(4,5)P2 using an in vitro kinase reaction. The product of this reaction can be selectively detected and quantified with high sensitivity using a liquid chromatography-tandem mass spectrometry platform. Further, using this method, we capture and quantify the unique acyl chain composition of PI5P from Drosophila cells and tissues. Finally, we demonstrate the use of this technique to quantify elevations in PI5P levels, from both Drosophila larval tissues and cultured cells depleted of phosphatidylinositol 5 phosphate 4-kinase (PIP4K), that metabolizes PI5P into PI(4,5)P2 thus regulating its levels. Thus, we demonstrate the potential of our method to quantify PI5P levels with high sensitivity levels from cells and tissues of multicellular organisms thus accelerating understanding of PI5P functions in vivo.

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Regulation of PI4P levels by PI4KIIIα during G-protein-coupled PLC signaling in Drosophila photoreceptors

Cited by 28 publications

References 37 publications

A Cytoplasmic GOLD Protein Controls Cell Polarity

A Cytoplasmic GOLD Protein Controls Cell Polarity

Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

A novel mass assay to measure phosphatidylinositol-5-phosphate from cells and tissues

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