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Journal articles on the topic 'PI4KIIIα'

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Published: 9 March 2023
Last updated: 10 March 2023

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1

Zólyomi, Annamária, Xiaohang Zhao, Gregory J. Downing, and Tamas Balla. "Localization of two distinct type III phosphatidylinositol 4-kinase enzyme mRNAs in the rat." American Journal of Physiology-Cell Physiology 278, no. 5 (May 1, 2000): C914—C920. http://dx.doi.org/10.1152/ajpcell.2000.278.5.c914.

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Inositol lipid kinases generate polyphosphoinositides, important regulators of several cellular functions. We have recently cloned two distinct phosphatidylinositol (PI) 4-kinase enzymes, the 210-kDa PI4KIIIα and the 110-kDa PI4KIIIβ, from bovine tissues. In the present study, the distribution of mRNAs encoding these two enzymes was analyzed by in situ hybridization histochemistry in the rat. PI4KIIIα was found predominantly expressed in the brain, with low expression in peripheral tissues. PI4KIIIβ was more uniformly expressed being also present in various peripheral tissues. Within the brain, PI4KIIIβ showed highest expression in the gray matter, especially in neurons of the olfactory bulb and the hippocampus, but also gave a signal in the white matter indicating its presence in glia. PI4KIIIα was highly expressed in neurons, but lacked a signal in the white matter and the choroid plexus. Both enzymes showed expression in the pigment layer and nuclear layers as well as in the ganglion cells of the retina. In a 17-day-old rat fetus, PI4KIIIβ was found to be more widely distributed and PI4KIIIα was primarily expressed in neurons. These results indicate that PI4KIIIβ is more widely expressed than PI4KIIIα, and that the two enzymes are probably coexpressed in many neurons. Such expression pattern and the conservation of these two proteins during evolution suggest their nonredundant functions in mammalian cells.
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2

Balla, Andras, Galina Tuymetova, Arnold Tsiomenko, Péter Várnai, and Tamas Balla. "A Plasma Membrane Pool of Phosphatidylinositol 4-Phosphate Is Generated by Phosphatidylinositol 4-Kinase Type-III Alpha: Studies with the PH Domains of the Oxysterol Binding Protein and FAPP1." Molecular Biology of the Cell 16, no. 3 (March 2005): 1282–95. http://dx.doi.org/10.1091/mbc.e04-07-0578.

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The PH domains of OSBP and FAPP1 fused to GFP were used to monitor PI(4)P distribution in COS-7 cells during manipulations of PI 4-kinase (PI4K) activities. Both domains were associated with the Golgi and small cytoplasmic vesicles, and a small fraction of OSBP-PH was found at the plasma membrane (PM). Inhibition of type-III PI4Ks with 10 μM wortmannin (Wm) significantly reduced but did not abolish Golgi localization of either PH domains. Downregulation of PI4KIIα or PI4KIIIβ by siRNA reduced the localization of the PH domains to the Golgi and in the former case any remaining Golgi localization was eliminated by Wm treatment. PLC activation by Ca2+ ionophores dissociated the domains from all membranes, but after Ca2+ chelation, they rapidly reassociated with the Golgi, the intracellular vesicles and with the PM. PM association of the domains was significantly higher after the Ca2+ transient and was abolished by Wm pretreatment. PM relocalization was not affected by down-regulation of PI4KIIIβ or -IIα, but was inhibited by down-regulation of PI4KIIIα, or by 10 μM PAO, which also inhibits PI4KIIIα. Our data suggest that these PH domains detect PI(4)P formation in extra-Golgi compartments under dynamic conditions and that various PI4Ks regulate PI(4)P synthesis in distinct cellular compartments.
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3

Reghellin, V., L. Donnici, S. Fenu, V. Berno, V. Calabrese, M. Pagani, S. Abrignani, F. Peri, R. De Francesco, and P. Neddermann. "NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes." Antimicrobial Agents and Chemotherapy 58, no. 12 (September 15, 2014): 7128–40. http://dx.doi.org/10.1128/aac.03293-14.

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ABSTRACTThe hepatitis C virus (HCV) nonstructural (NS) protein 5A is a multifunctional protein that plays a central role in viral replication and assembly. Antiviral agents directly targeting NS5A are currently in clinical development. Although the elucidation of the mechanism of action (MOA) of NS5A inhibitors has been the focus of intensive research, a detailed understanding of how these agents exert their antiviral effect is still lacking. In this study, we observed that the downregulation of NS5A hyperphosphorylation is associated with the actions of NS5A inhibitors belonging to different chemotypes. NS5A is known to recruit the lipid kinase phosphatidylinositol 4-kinase IIIα (PI4KIIIα) to the HCV-induced membranous web in order to generate phosphatidylinositol 4-phosphate (PI4P) at the sites of replication. We demonstrate that treatment with NS5A inhibitors leads to an impairment in the NS5A-PI4KIIIα complex formation that is paralleled by a significant reduction in PI4P and cholesterol levels within the endomembrane structures of HCV-replicating cells. A similar decrease in PI4P and cholesterol levels was also obtained upon treatment with a PI4KIIIα-targeting inhibitor. In addition, both the NS5A and PI4KIIIα classes of inhibitors induced similar subcellular relocalization of the NS5A protein, causing the formation of large cytoplasmic NS5A-containing clusters previously reported to be one of the hallmarks of inhibition of the action of PI4KIIIα. Because of the similarities between the effects induced by treatment with PI4KIIIα or NS5A inhibitors and the observation that agents targeting NS5A impair NS5A-PI4KIIIα complex formation, we speculate that NS5A inhibitors act by interfering with the function of the NS5A-PI4KIIIα complex.
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4

Tian, Shuaizhen, Jinzhe Zeng, Xiao Liu, Jianzhong Chen, John Z. H. Zhang, and Tong Zhu. "Understanding the selectivity of inhibitors toward PI4KIIIα and PI4KIIIβ based molecular modeling." Physical Chemistry Chemical Physics 21, no. 39 (2019): 22103–12. http://dx.doi.org/10.1039/c9cp03598b.

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5

Nakatsu, Fubito, Jeremy M. Baskin, Jeeyun Chung, Lukas B. Tanner, Guanghou Shui, Sang Yoon Lee, Michelle Pirruccello, et al. "PtdIns4P synthesis by PI4KIIIα at the plasma membrane and its impact on plasma membrane identity." Journal of Cell Biology 199, no. 6 (December 10, 2012): 1003–16. http://dx.doi.org/10.1083/jcb.201206095.

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Plasma membrane phosphatidylinositol (PI) 4-phosphate (PtdIns4P) has critical functions via both direct interactions and metabolic conversion to PI 4,5-bisphosphate (PtdIns(4,5)P2) and other downstream metabolites. However, mechanisms that control this PtdIns4P pool in cells of higher eukaryotes remain elusive. PI4KIIIα, the enzyme thought to synthesize this PtdIns4P pool, is reported to localize in the ER, contrary to the plasma membrane localization of its yeast homologue, Stt4. In this paper, we show that PI4KIIIα was targeted to the plasma membrane as part of an evolutionarily conserved complex containing Efr3/rolling blackout, which we found was a palmitoylated peripheral membrane protein. PI4KIIIα knockout cells exhibited a profound reduction of plasma membrane PtdIns4P but surprisingly only a modest reduction of PtdIns(4,5)P2 because of robust up-regulation of PtdIns4P 5-kinases. In these cells, however, much of the PtdIns(4,5)P2 was localized intracellularly, rather than at the plasma membrane as in control cells, along with proteins typically restricted to this membrane, revealing a major contribution of PI4KIIIα to the definition of plasma membrane identity.
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6

Balla, Andras, Yeun Ju Kim, Peter Varnai, Zsofia Szentpetery, Zachary Knight, Kevan M. Shokat, and Tamas Balla. "Maintenance of Hormone-sensitive Phosphoinositide Pools in the Plasma Membrane Requires Phosphatidylinositol 4-Kinase IIIα." Molecular Biology of the Cell 19, no. 2 (February 2008): 711–21. http://dx.doi.org/10.1091/mbc.e07-07-0713.

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Type III phosphatidylinositol (PtdIns) 4-kinases (PI4Ks) have been previously shown to support plasma membrane phosphoinositide synthesis during phospholipase C activation and Ca2+ signaling. Here, we use biochemical and imaging tools to monitor phosphoinositide changes in the plasma membrane in combination with pharmacological and genetic approaches to determine which of the type III PI4Ks (α or β) is responsible for supplying phosphoinositides during agonist-induced Ca2+ signaling. Using inhibitors that discriminate between the α- and β-isoforms of type III PI4Ks, PI4KIIIα was found indispensable for the production of phosphatidylinositol 4-phosphate (PtdIns4P), phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], and Ca2+ signaling in angiotensin II (AngII)-stimulated cells. Down-regulation of either the type II or type III PI4K enzymes by small interfering RNA (siRNA) had small but significant effects on basal PtdIns4P and PtdIns(4,5)P2 levels in 32P-labeled cells, but only PI4KIIIα down-regulation caused a slight impairment of PtdIns4P and PtdIns(4,5)P2 resynthesis in AngII-stimulated cells. None of the PI4K siRNA treatments had a measurable effect on AngII-induced Ca2+ signaling. These results indicate that a small fraction of the cellular PI4K activity is sufficient to maintain plasma membrane phosphoinositide pools, and they demonstrate the value of the pharmacological approach in revealing the pivotal role of PI4KIIIα enzyme in maintaining plasma membrane phosphoinositides.
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7

Alli-Balogun, Ganiyu Olabanji, Christina A. Gewinner, Ruth Jacobs, Janos Kriston-Vizi, Mark G. Waugh, and Shane Minogue. "Phosphatidylinositol 4-kinase IIβ negatively regulates invadopodia formation and suppresses an invasive cellular phenotype." Molecular Biology of the Cell 27, no. 25 (December 15, 2016): 4033–42. http://dx.doi.org/10.1091/mbc.e16-08-0564.

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The type II phosphatidylinositol 4-kinase (PI4KII) enzymes synthesize the lipid phosphatidylinositol 4-phosphate (PI(4)P), which has been detected at the Golgi complex and endosomal compartments and recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear. We found that depletion of PI4KIIα and PI4KIIβ using small interfering RNA led to actin remodeling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP). Depletion of PI4KII isoforms also differentially affected trans-Golgi network (TGN) pools of PI(4)P and post-TGN traffic. PI4KIIβ depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalization of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7 but increased localization with the exocytic Rab8. Depletion of PI4KIIβ was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIβ mRNA are associated with human cancers. This finding supports the cell data and suggests that PI4KIIβ may be a clinically significant suppressor of invasion. We propose that PI4KIIβ synthesizes a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia.
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8

Lees, Joshua A., Yixiao Zhang, Michael S. Oh, Curtis M. Schauder, Xiaoling Yu, Jeremy M. Baskin, Kerry Dobbs, et al. "Architecture of the human PI4KIIIα lipid kinase complex." Proceedings of the National Academy of Sciences 114, no. 52 (December 11, 2017): 13720–25. http://dx.doi.org/10.1073/pnas.1718471115.

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Plasma membrane (PM) phosphoinositides play essential roles in cell physiology, serving as both markers of membrane identity and signaling molecules central to the cell’s interaction with its environment. The first step in PM phosphoinositide synthesis is the conversion of phosphatidylinositol (PI) to PI4P, the precursor of PI(4,5)P2 and PI(3,4,5)P3. This conversion is catalyzed by the PI4KIIIα complex, comprising a lipid kinase, PI4KIIIα, and two regulatory subunits, TTC7 and FAM126. We here report the structure of this complex at 3.6-Å resolution, determined by cryo-electron microscopy. The proteins form an obligate ∼700-kDa superassembly with a broad surface suitable for membrane interaction, toward which the kinase active sites are oriented. The structural complexity of the assembly highlights PI4P synthesis as a major regulatory junction in PM phosphoinositide homeostasis. Our studies provide a framework for further exploring the mechanisms underlying PM phosphoinositide regulation.
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9

Jović, Marko, Michelle J. Kean, Zsofia Szentpetery, Gordon Polevoy, Anne-Claude Gingras, Julie A. Brill, and Tamas Balla. "Two phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, β-glucocerebrosidase." Molecular Biology of the Cell 23, no. 8 (April 15, 2012): 1533–45. http://dx.doi.org/10.1091/mbc.e11-06-0553.

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Gaucher disease is a lysosomal storage disorder caused by a defect in the degradation of glucosylceramide catalyzed by the lysosomal enzyme β-glucocerebrosidase (GBA). GBA reaches lysosomes via association with its receptor, lysosomal integral membrane protein type 2 (LIMP-2). We found that distinct phosphatidylinositol 4-kinases (PI4Ks) play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi caused accumulation of LIMP-2 in this compartment, and PI4KIIIβ was found to be responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIα blocked trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIα depletion also caused secretion of missorted GBA into the medium, which was attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIβ inhibitors. These studies identified PI4KIIIβ and PI4KIIα as important regulators of lysosomal delivery of GBA, revealing a new element of control to sphingolipid homeostasis by phosphoinositides.
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10

Banerji, Sangeeta, Mike Ngo, Ciaran F. Lane, Carolyn-Ann Robinson, Shane Minogue, and Neale D. Ridgway. "Oxysterol Binding Protein-dependent Activation of Sphingomyelin Synthesis in the Golgi Apparatus Requires Phosphatidylinositol 4-Kinase IIα." Molecular Biology of the Cell 21, no. 23 (December 2010): 4141–50. http://dx.doi.org/10.1091/mbc.e10-05-0424.

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Cholesterol and sphingomyelin (SM) associate in raft domains and are metabolically coregulated. One aspect of coordinate regulation occurs in the Golgi apparatus where oxysterol binding protein (OSBP) mediates sterol-dependent activation of ceramide transport protein (CERT) activity and SM synthesis. Because CERT transfer activity is dependent on its phosphatidylinositol 4 phosphate [PtdIns(4)P]-specific pleckstrin homology domain, we investigated whether OSBP activation of CERT involved a Golgi-associated PtdIns 4-kinase (PI4K). Cell fractionation experiments revealed that Golgi/endosome-enriched membranes from 25-hydroxycholesterol-treated Chinese hamster ovary cells had increased activity of a sterol-sensitive PI4K that was blocked by small interfering RNA silencing of OSBP. Consistent with this sterol-requirement, OSBP silencing also reduced the cholesterol content of endosome/trans-Golgi network (TGN) fractions containing PI4KIIα. PI4KIIα, but not PI4KIIIβ, was required for oxysterol-activation of SM synthesis and recruitment of CERT to the Golgi apparatus. However, neither PI4KIIα nor PI4KIIIβ expression was required for 25-hydroxycholesterol–dependent translocation of OSBP to the Golgi apparatus. The presence of OSBP, CERT, and PI4KIIα in the TGN of oxysterol-stimulated cells suggests that OSBP couples sterol binding or transfer activity with regulation of PI4KIIα activity, leading to CERT recruitment to the TGN and increased SM synthesis.
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11

Guo, Zhenzhen, Chao-Hua Jiang, Chunfang Tong, Yanrui Yang, Zehua Wang, Sin Man Lam, Dou Wang, et al. "Activity-dependent PI4P synthesis by PI4KIIIα regulates long-term synaptic potentiation." Cell Reports 38, no. 9 (March 2022): 110452. http://dx.doi.org/10.1016/j.celrep.2022.110452.

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12

Bura, Ana, and Antonija Jurak Begonja. "Imaging of Intracellular and Plasma Membrane Pools of PI(4,5)P2 and PI4P in Human Platelets." Life 11, no. 12 (December 1, 2021): 1331. http://dx.doi.org/10.3390/life11121331.

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Phosphoinositides (PIs) are phosphorylated membrane lipids that have a plethora of roles in the cell, including vesicle trafficking, signaling, and actin reorganization. The most abundant PIs in the cell are phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol-4-monophosphate (PI4P). The localization and roles of both PI(4,5)P2 and PI4P are well established, is the broadly accepted methodological approach for their immunocytochemical visualization in different cell compartments in several cell lines. However, not much is known about these PIs in platelets (PLTs), the smallest blood cells that detect vessel wall injury, activate, and stop the bleeding. Therefore, we sought to investigate the localization of PI(4,5)P2 and PI4P in resting and activated PLTs by antibody staining. Here, we show that the intracellular pools of PI(4,5)P2 and PI4P can be detected by the established staining protocol, and these pools can be modulated by inhibitors of OCRL phosphatase and PI4KIIIα kinase. However, although resting PLTs readily stain for the plasma membrane (PM) pools of PI(4,5)P2 and PI4P, just a few activated cells were stained with the established protocol. We show that optimized protocol allows for the visualization of PI(4,5)P2 and PI4P at PM in activated PLTs, which could also be modulated by OCRL and PI4KIIIα inhibitors. We conclude that PI(4,5)P2 and PI4P are more sensitive to lipid extraction by permeabilizing agents in activated than in resting human PLTs, which suggests their different roles during PLT activation.
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13

Waugh, Mark G. "The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer)." Biochemical Journal 476, no. 16 (August 28, 2019): 2321–46. http://dx.doi.org/10.1042/bcj20180622.

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Abstract Phosphatidylinositol 4-phosphate (PI4P) is a membrane glycerophospholipid and a major regulator of the characteristic appearance of the Golgi complex as well as its vesicular trafficking, signalling and metabolic functions. Phosphatidylinositol 4-kinases, and in particular the PI4KIIIβ isoform, act in concert with PI4P to recruit macromolecular complexes to initiate the biogenesis of trafficking vesicles for several Golgi exit routes. Dysregulation of Golgi PI4P metabolism and the PI4P protein interactome features in many cancers and is often associated with tumour progression and a poor prognosis. Increased expression of PI4P-binding proteins, such as GOLPH3 or PITPNC1, induces a malignant secretory phenotype and the release of proteins that can remodel the extracellular matrix, promote angiogenesis and enhance cell motility. Aberrant Golgi PI4P metabolism can also result in the impaired post-translational modification of proteins required for focal adhesion formation and cell–matrix interactions, thereby potentiating the development of aggressive metastatic and invasive tumours. Altered expression of the Golgi-targeted PI 4-kinases, PI4KIIIβ, PI4KIIα and PI4KIIβ, or the PI4P phosphate Sac1, can also modulate oncogenic signalling through effects on TGN-endosomal trafficking. A Golgi trafficking role for a PIP 5-kinase has been recently described, which indicates that PI4P is not the only functionally important phosphoinositide at this subcellular location. This review charts new developments in our understanding of phosphatidylinositol 4-kinase function at the Golgi and how PI4P-dependent trafficking can be deregulated in malignant disease.
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14

Zheng, Linan, Feng Hong, Fude Huang, and Wenan Wang. "Inhibition of PI4KIIIα as a Novel Potential Approach for Gaucher Disease Treatment." Neuroscience Bulletin 37, no. 8 (May 21, 2021): 1234–39. http://dx.doi.org/10.1007/s12264-021-00704-w.

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15

Sbrissa, Diego, Louie Semaan, Barani Govindarajan, Yanfeng Li, Nicholas J. Caruthers, Paul M. Stemmer, Michael L. Cher, et al. "A novel cross-talk between CXCR4 and PI4KIIIα in prostate cancer cells." Oncogene 38, no. 3 (August 15, 2018): 332–44. http://dx.doi.org/10.1038/s41388-018-0448-0.

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16

Dornan, Gillian L., Udit Dalwadi, David J. Hamelin, Reece M. Hoffmann, Calvin K. Yip, and John E. Burke. "Probing the Architecture, Dynamics, and Inhibition of the PI4KIIIα/TTC7/FAM126 Complex." Journal of Molecular Biology 430, no. 18 (September 2018): 3129–42. http://dx.doi.org/10.1016/j.jmb.2018.07.020.

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17

Shi, Lei, Xiaochao Tan, Xin Liu, Jiang Yu, Neus Bota-Rabassedas, Yichi Niu, Jiayi Luo, et al. "Addiction to Golgi-resident PI4P synthesis in chromosome 1q21.3–amplified lung adenocarcinoma cells." Proceedings of the National Academy of Sciences 118, no. 25 (June 21, 2021): e2023537118. http://dx.doi.org/10.1073/pnas.2023537118.

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A chromosome 1q21.3 region that is frequently amplified in diverse cancer types encodes phosphatidylinositol (PI)-4 kinase IIIβ (PI4KIIIβ), a key regulator of secretory vesicle biogenesis and trafficking. Chromosome 1q21.3–amplified lung adenocarcinoma (1q-LUAD) cells rely on PI4KIIIβ for Golgi-resident PI-4-phosphate (PI4P) synthesis, prosurvival effector protein secretion, and cell viability. Here, we show that 1q-LUAD cells subjected to prolonged PI4KIIIβ antagonist treatment acquire tolerance by activating an miR-218-5p–dependent competing endogenous RNA network that up-regulates PI4KIIα, which provides an alternative source of Golgi-resident PI4P that maintains prosurvival effector protein secretion and cell viability. These findings demonstrate an addiction to Golgi-resident PI4P synthesis in a genetically defined subset of cancers.
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18

Jung, Gwanghyun, Jing Wang, Pawel Wlodarski, Barbara Barylko, Derk D. Binns, Hongjun Shu, Helen L. Yin, and Joseph P. Albanesi. "Molecular determinants of activation and membrane targeting of phosphoinositol 4-kinase IIβ." Biochemical Journal 409, no. 2 (December 21, 2007): 501–9. http://dx.doi.org/10.1042/bj20070821.

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Mammalian cells contain two isoforms of the type II PI4K (phosphoinositol 4-kinase), PI4KIIα and β. These 55 kDa proteins have highly diverse N-terminal regions (approximately residues 1–90) but conserved catalytic domains (approximately from residue 91 to the C-termini). Nearly the entire pool of PI4KIIα behaves as an integral membrane protein, in spite of a lack of a transmembrane domain. This integral association with membranes is due to palmitoylation of a cysteine-rich motif, CCPCC, located within the catalytic domain. Although the CCPCC motif is conserved in PI4KIIβ, only 50% of PI4KIIβ is membrane-associated, and approximately half of this pool is only peripherally attached to the membranes. Growth factor stimulation or overexpression of a constitutively active Rac mutant induces the translocation of a portion of cytosolic PI4KIIβ to plasma membrane ruffles and stimulates its activity. Here, we demonstrate that membrane-associated PI4KIIβ undergoes two modifications, palmitoylation and phosphorylation. The cytosolic pool of PI4KIIβ is not palmitoylated and has much lower lipid kinase activity than the membrane-associated kinase. Although only membrane-associated PI4KIIβ is phosphorylated in the unique N-terminal region, this modification apparently does not influence its membrane binding or activity. A series of truncation mutants and α/β chimaeras were generated to identify regions responsible for the isoform-specific behaviour of the kinases. Surprisingly, the C-terminal approx. 160 residues, and not the diverse N-terminal regions, contain the sites that are most important in determining the different solubilities, palmitoylation states and stimulus-dependent redistributions of PI4KIIα and β.
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Balakrishnan, Sruthi S., Urbashi Basu, Dhananjay Shinde, Rajan Thakur, Manish Jaiswal, and Padinjat Raghu. "Regulation of PI4P levels by PI4KIIIα during G-protein-coupled PLC signaling inDrosophilaphotoreceptors." Journal of Cell Science 131, no. 15 (July 6, 2018): jcs217257. http://dx.doi.org/10.1242/jcs.217257.

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20

Basu, Urbashi, Sruthi S. Balakrishnan, Vishnu Janardan, and Padinjat Raghu. "A PI4KIIIα protein complex is required for cell viability during Drosophila wing development." Developmental Biology 462, no. 2 (June 2020): 208–22. http://dx.doi.org/10.1016/j.ydbio.2020.03.008.

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21

Wang, Chen, Ya Gao, Jiaying Gu, Huimin Chen, Zhixiang Yin, Hao Zhu, and Tong Zhu. "Ensemble-based virtual screening of human PI4KIIIα inhibitors toward the Hepatitis C virus." Chemical Physics Letters 815 (March 2023): 140354. http://dx.doi.org/10.1016/j.cplett.2023.140354.

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22

Wang, Hanzhi, Hui-Qiao Sun, Xiaohui Zhu, Li Zhang, Joseph Albanesi, Beth Levine, and Helen Yin. "GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion." Proceedings of the National Academy of Sciences 112, no. 22 (May 18, 2015): 7015–20. http://dx.doi.org/10.1073/pnas.1507263112.

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The Atg8 autophagy proteins are essential for autophagosome biogenesis and maturation. The γ-aminobutyric acid receptor-associated protein (GABARAP) Atg8 family is much less understood than the LC3 Atg8 family, and the relationship between the GABARAPs’ previously identified roles as modulators of transmembrane protein trafficking and autophagy is not known. Here we report that GABARAPs recruit palmitoylated PI4KIIα, a lipid kinase that generates phosphatidylinositol 4-phosphate (PI4P) and binds GABARAPs, from the perinuclear Golgi region to autophagosomes to generate PI4P in situ. Depletion of either GABARAP or PI4KIIα, or overexpression of a dominant-negative kinase-dead PI4KIIα mutant, decreases autophagy flux by blocking autophagsome:lysosome fusion, resulting in the accumulation of abnormally large autophagosomes. The autophagosome defects are rescued by overexpressing PI4KIIα or by restoring intracellular PI4P through “PI4P shuttling.” Importantly, PI4KIIα’s role in autophagy is distinct from that of PI4KIIIβ and is independent of subsequent phosphatidylinositol 4,5 biphosphate (PIP2) generation. Thus, GABARAPs recruit PI4KIIα to autophagosomes, and PI4P generation on autophagosomes is critically important for fusion with lysosomes. Our results establish that PI4KIIα and PI4P are essential effectors of the GABARAP interactome’s fusion machinery.
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23

Bilodeau, Patricia, Daniel Jacobsen, Denise Law-Vinh, and Jonathan M. Lee. "Phosphatidylinositol 4-kinase III beta regulates cell shape, migration, and focal adhesion number." Molecular Biology of the Cell 31, no. 17 (August 1, 2020): 1904–16. http://dx.doi.org/10.1091/mbc.e19-11-0600.

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This work describes a role for the lipid phosphatidylinositol 4-phosphate (PI4P) and lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) in cell motility, cell shape, and focal adhesion (FA) formation. During fibroblast migration, PI4P vesicles move to the leading edge and fuse with FA there. Deletion of PI4KIIIB impairs fibroblast migration, increases the number of FA, and alters cell shape.
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López-Haber, Cynthia, Roni Levin-Konigsberg, Yueyao Zhu, Jing Bi-Karchin, Tamas Balla, Sergio Grinstein, Michael S. Marks, and Adriana R. Mantegazza. "Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells." Proceedings of the National Academy of Sciences 117, no. 45 (October 27, 2020): 28251–62. http://dx.doi.org/10.1073/pnas.2001948117.

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Toll-like receptor (TLR) recruitment to phagosomes in dendritic cells (DCs) and downstream TLR signaling are essential to initiate antimicrobial immune responses. However, the mechanisms underlying TLR localization to phagosomes are poorly characterized. We show herein that phosphatidylinositol-4-kinase IIα (PI4KIIα) plays a key role in initiating phagosomal TLR4 responses in murine DCs by generating a phosphatidylinositol-4-phosphate (PtdIns4P) platform conducive to the binding of the TLR sorting adaptor Toll-IL1 receptor (TIR) domain-containing adaptor protein (TIRAP). PI4KIIα is recruited to maturing lipopolysaccharide (LPS)-containing phagosomes in an adaptor protein-3 (AP-3)-dependent manner, and both PI4KIIα and PtdIns4P are detected on phagosomal membrane tubules. Knockdown of PI4KIIα—but not the related PI4KIIβ—impairs TIRAP and TLR4 localization to phagosomes, reduces proinflammatory cytokine secretion, abolishes phagosomal tubule formation, and impairs major histocompatibility complex II (MHC-II) presentation. Phagosomal TLR responses in PI4KIIα-deficient DCs are restored by reexpression of wild-type PI4KIIα, but not of variants lacking kinase activity or AP-3 binding. Our data indicate that PI4KIIα is an essential regulator of phagosomal TLR signaling in DCs by ensuring optimal TIRAP recruitment to phagosomes.
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Zhang, Xiao, Wen-An Wang, Li-Xiang Jiang, Hai-Yan Liu, Bao-Zhu Zhang, Nastasia Lim, Qing-Yi Li, and Fu-De Huang. "Downregulation of RBO-PI4KIIIα Facilitates Aβ42 Secretion and Ameliorates Neural Deficits in Aβ42-Expressing Drosophila." Journal of Neuroscience 37, no. 19 (April 19, 2017): 4928–41. http://dx.doi.org/10.1523/jneurosci.3567-16.2017.

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Reiss, S., C. Harak, I. Romero-Brey, I. Rebhan, D. Radujkovic, R. Bartenschlager, and V. Lohmann. "129 MODULATION OF PHOSPHORYLATION OF HEPATITIS C VIRUS NONSTRUCTURAL PROTEIN 5A BY THE LIPID KINASE PI4KIIIα." Journal of Hepatology 56 (April 2012): S56. http://dx.doi.org/10.1016/s0168-8278(12)60143-3.

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Tham, To Nam, Edith Gouin, Eric Rubinstein, Claude Boucheix, Pascale Cossart, and Javier Pizarro-Cerda. "Tetraspanin CD81 Is Required for Listeria monocytogenes Invasion." Infection and Immunity 78, no. 1 (November 9, 2009): 204–9. http://dx.doi.org/10.1128/iai.00661-09.

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ABSTRACT Listeria monocytogenes is an intracellular bacterial pathogen that invades epithelial cells by subverting two cellular receptors, E-cadherin and Met. We recently identified type II phosphatidylinositol 4-kinases α and β (PI4KIIα and PI4KIIβ) as being required for bacterial entry downstream of Met. In this work, we investigated whether tetraspanins CD9, CD63, and CD81, which figure among the few described molecular partners of PI4KIIα, function as molecular adaptors recruiting PI4KIIα to the bacterial entry site. We observed by fluorescence microscopy that CD9, CD63, and CD81 are expressed and detected at the cellular surface and also within intracellular compartments, particularly in the case of CD63. In resting cells, colocalization of tetraspanins and PI4KIIα is detectable only in restricted areas of the perinuclear region. Upon infection with Listeria, endogenous CD9, CD63, and CD81 were recruited to the bacterial entry site but did not colocalize strictly with endogenous PI4KIIα. Live-cell imaging confirmed that tetraspanins and PI4KIIα do not follow the same recruitment dynamics to the Listeria entry site. Depletion of CD9, CD63, and CD81 levels by small interfering RNA demonstrated that CD81 is required for bacterial internalization, identifying for the first time a role for a member of the tetraspanin family in the entry of Listeria into target cells. Moreover, depletion of CD81 inhibits the recruitment of PI4KIIα but not that of the Met receptor to the bacterial entry site, suggesting that CD81 may act as a membrane organizer required for the integrity of signaling events occurring at Listeria entry sites.
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Noji, Satoru, Noriyoshi Seki, Takaki Maeba, Takayuki Sakai, Eiichi Watanabe, Katsuya Maeda, Kyoko Fukushima, et al. "Concise SAR Exploration Based on the “Head-to-Tail” Approach: Discovery of PI4KIIIα Inhibitors Bearing Diverse Scaffolds." ACS Medicinal Chemistry Letters 7, no. 10 (August 16, 2016): 919–23. http://dx.doi.org/10.1021/acsmedchemlett.6b00232.

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29

Raubo, Piotr, David M. Andrews, Jennifer C. McKelvie, Graeme R. Robb, James M. Smith, Martin E. Swarbrick, and Michael J. Waring. "Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα)." Bioorganic & Medicinal Chemistry Letters 25, no. 16 (August 2015): 3189–93. http://dx.doi.org/10.1016/j.bmcl.2015.05.093.

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30

Kattan, Walaa E., Wei Chen, Xiaoping Ma, Tien Hung Lan, Dharini van der Hoeven, Ransome van der Hoeven, and John F. Hancock. "Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function." Life Science Alliance 2, no. 5 (August 26, 2019): e201900431. http://dx.doi.org/10.26508/lsa.201900431.

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The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We, therefore, investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidyl-4-phosphate synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion significantly reduced proliferation and anchorage-independent growth of multiple KRAS-dependent cancer cell lines, and attenuated KRAS signaling in vivo. Similarly, functionally inhibiting ORP5 and ORP8 by inhibiting PI4KIIIα-mediated synthesis of phosphatidyl-4-phosphate at the PM selectively inhibited the growth of KRAS-dependent cancer cell lines over normal cells. Inhibiting KRAS function through regulating PM lipid PtdSer content may represent a viable strategy for KRAS-driven cancers.
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Leivers, Anna L., Matthew Tallant, J. Brad Shotwell, Scott Dickerson, Martin R. Leivers, Octerloney B. McDonald, Jeff Gobel, et al. "Discovery of Selective Small Molecule Type III Phosphatidylinositol 4-Kinase Alpha (PI4KIIIα) Inhibitors as Anti Hepatitis C (HCV) Agents." Journal of Medicinal Chemistry 57, no. 5 (August 14, 2013): 2091–106. http://dx.doi.org/10.1021/jm400781h.

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32

Chu, K. M. E., S. Minogue, J. J. Hsuan, and M. G. Waugh. "Differential effects of the phosphatidylinositol 4-kinases, PI4KIIα and PI4KIIIβ, on Akt activation and apoptosis." Cell Death & Disease 1, no. 12 (December 2010): e106-e106. http://dx.doi.org/10.1038/cddis.2010.84.

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33

Zhang, Qichao, Baozhu Zhang, Nastasia K. H. Lim, Xiao Zhang, Shiquan Meng, Jens R. Nyengaard, Fude Huang, and Wen-An Wang. "Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila." Biochemical and Biophysical Research Communications 589 (January 2022): 71–77. http://dx.doi.org/10.1016/j.bbrc.2021.11.106.

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34

Chatterji, Udayan, Michael Bobardt, Andrew Tai, Malcolm Wood, and Philippe A. Gallay. "Cyclophilin and NS5A Inhibitors, but Not Other Anti-Hepatitis C Virus (HCV) Agents, Preclude HCV-Mediated Formation of Double-Membrane-Vesicle Viral Factories." Antimicrobial Agents and Chemotherapy 59, no. 5 (February 9, 2015): 2496–507. http://dx.doi.org/10.1128/aac.04958-14.

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ABSTRACTAlthough the mechanisms of action (MoA) of nonstructural protein 3 inhibitors (NS3i) and NS5B inhibitors (NS5Bi) are well understood, the MoA of cyclophilin inhibitors (CypI) and NS5A inhibitors (NS5Ai) are not fully defined. In this study, we examined whether CypI and NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis of replication complexes (RCs) or with an earlier step of HCV RNA replication, the creation of double-membrane vesicles (DMVs) essential for HCV RNA replication. In contrast to NS5Bi, both CypI and NS5Ai do not block HCV RNA synthesis by way of RCs, suggesting that they exert their antiviral activity prior to the establishment of enzymatically active RCs. We found that viral replication is not a precondition for DMV formation, since the NS3-NS5B polyprotein or NS5A suffices to create DMVs. Importantly, only CypI and NS5Ai, but not NS5Bi, mir-122, or phosphatidylinositol-4 kinase IIIα (PI4KIIIα) inhibitors, prevent NS3-NS5B-mediated DMV formation. NS3-NS5B was unable to create DMVs in cyclophilin A (CypA) knockdown (KD) cells. We also found that the isomerase activity of CypA is absolutely required for DMV formation. This not only suggests that NS5A and CypA act in concert to build membranous viral factories but that CypI and NS5Ai mediate their early anti-HCV effects by preventing the formation of organelles, where HCV replication is normally initiated. This is the first investigation to examine the effect of a large panel of anti-HCV agents on DMV formation, and the results reveal that CypI and NS5Ai act at the same membranous web biogenesis step of HCV RNA replication, thus indicating a new therapeutic target of chronic hepatitis C.
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Craige, Branch, Gloria Salazar, and Victor Faundez. "Phosphatidylinositol-4-Kinase Type II Alpha Contains an AP-3–sorting Motif and a Kinase Domain That Are Both Required for Endosome Traffic." Molecular Biology of the Cell 19, no. 4 (April 2008): 1415–26. http://dx.doi.org/10.1091/mbc.e07-12-1239.

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The adaptor complex 3 (AP-3) targets membrane proteins from endosomes to lysosomes, lysosome-related organelles and synaptic vesicles. Phosphatidylinositol-4-kinase type II α (PI4KIIα) is one of several proteins possessing catalytic domains that regulate AP-3–dependent sorting. Here we present evidence that PI4KIIα uniquely behaves both as a membrane protein cargo as well as an enzymatic regulator of adaptor function. In fact, AP-3 and PI4KIIα form a complex that requires a dileucine-sorting motif present in PI4KIIα. Mutagenesis of either the PI4KIIα-sorting motif or its kinase-active site indicates that both are necessary to interact with AP-3 and properly localize PI4KIIα to LAMP-1–positive endosomes. Similarly, both the kinase activity and the sorting signal present in PI4KIIα are necessary to rescue endosomal PI4KIIα siRNA-induced mutant phenotypes. We propose a mechanism whereby adaptors use canonical sorting motifs to selectively recruit a regulatory enzymatic activity to restricted membrane domains.
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36

Dorobantu, Cristina M., Lauren A. Ford-Siltz, Simone P. Sittig, Kjerstin H. W. Lanke, George A. Belov, Frank J. M. van Kuppeveld, and Hilde M. van der Schaar. "GBF1- and ACBD3-Independent Recruitment of PI4KIIIβ to Replication Sites by Rhinovirus 3A Proteins." Journal of Virology 89, no. 3 (November 19, 2014): 1913–18. http://dx.doi.org/10.1128/jvi.02830-14.

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PI4KIIIβ recruitment to Golgi membranes relies on GBF1/Arf and ACBD3. Enteroviruses such as poliovirus and coxsackievirus recruit PI4KIIIβ to their replication sites via their 3A proteins. Here, we show that human rhinovirus (HRV) 3A also recruited PI4KIIIβ to replication sites. Unlike other enterovirus 3A proteins, HRV 3A failed to bind GBF1. Although HRV 3A was previously shown to interact with ACBD3, our data suggest that PI4KIIIβ recruitment occurred independently of both GBF1 and ACBD3.
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37

Salazar, Gloria, Branch Craige, Bruce H. Wainer, Jun Guo, Pietro De Camilli, and Victor Faundez. "Phosphatidylinositol-4-Kinase Type II α Is a Component of Adaptor Protein-3-derived Vesicles." Molecular Biology of the Cell 16, no. 8 (August 2005): 3692–704. http://dx.doi.org/10.1091/mbc.e05-01-0020.

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A membrane fraction enriched in vesicles containing the adaptor protein (AP) -3 cargo zinc transporter 3 was generated from PC12 cells and was used to identify new components of these organelles by mass spectrometry. Proteins prominently represented in the fraction included AP-3 subunits, synaptic vesicle proteins, and lysosomal proteins known to be sorted in an AP-3-dependent way or to interact genetically with AP-3. A protein enriched in this fraction was phosphatidylinositol-4-kinase type IIα (PI4KIIα). Biochemical, pharmacological, and morphological analyses supported the presence of PI4KIIα in AP-3-positive organelles. Furthermore, the subcellular localization of PI4KIIα was altered in cells from AP-3-deficient mocha mutant mice. The PI4KIIα normally present both in perinuclear and peripheral organelles was substantially decreased in the peripheral membranes of AP-3-deficient mocha fibroblasts. In addition, as is the case for other proteins sorted in an AP-3-dependent way, PI4KIIα content was strongly reduced in nerve terminals of mocha hippocampal mossy fibers. The functional relationship between AP-3 and PI4KIIα was further explored by PI4KIIα knockdown experiments. Reduction of the cellular content of PI4KIIα strongly decreased the punctate distribution of AP-3 observed in PC12 cells. These results indicate that PI4KIIα is present on AP-3 organelles where it regulates AP-3 function.
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38

Ryder, P. V., R. Vistein, A. Gokhale, M. N. Seaman, M. A. Puthenveedu, and V. Faundez. "The WASH complex, an endosomal Arp2/3 activator, interacts with the Hermansky–Pudlak syndrome complex BLOC-1 and its cargo phosphatidylinositol-4-kinase type IIα." Molecular Biology of the Cell 24, no. 14 (July 15, 2013): 2269–84. http://dx.doi.org/10.1091/mbc.e13-02-0088.

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Vesicle biogenesis machinery components such as coat proteins can interact with the actin cytoskeleton for cargo sorting into multiple pathways. It is unknown, however, whether these interactions are a general requirement for the diverse endosome traffic routes. In this study, we identify actin cytoskeleton regulators as previously unrecognized interactors of complexes associated with the Hermansky–Pudlak syndrome. Two complexes mutated in the Hermansky–Pudlak syndrome, adaptor protein complex-3 and biogenesis of lysosome-related organelles complex-1 (BLOC-1), interact with and are regulated by the lipid kinase phosphatidylinositol-4-kinase type IIα (PI4KIIα). We therefore hypothesized that PI4KIIα interacts with novel regulators of these complexes. To test this hypothesis, we immunoaffinity purified PI4KIIα from isotope-labeled cell lysates to quantitatively identify interactors. Strikingly, PI4KIIα isolation preferentially coenriched proteins that regulate the actin cytoskeleton, including guanine exchange factors for Rho family GTPases such as RhoGEF1 and several subunits of the WASH complex. We biochemically confirmed several of these PI4KIIα interactions. Of importance, BLOC-1 complex, WASH complex, RhoGEF1, or PI4KIIα depletions altered the content and/or subcellular distribution of the BLOC-1–sensitive cargoes PI4KIIα, ATP7A, and VAMP7. We conclude that the Hermansky–Pudlak syndrome complex BLOC-1 and its cargo PI4KIIα interact with regulators of the actin cytoskeleton.
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39

Jeganathan, Sujeeve, Anne Morrow, Anahita Amiri, and Jonathan M. Lee. "Eukaryotic Elongation Factor 1A2 Cooperates with Phosphatidylinositol-4 Kinase III β To Stimulate Production of Filopodia through Increased Phosphatidylinositol-4,5 Bisphosphate Generation." Molecular and Cellular Biology 28, no. 14 (May 12, 2008): 4549–61. http://dx.doi.org/10.1128/mcb.00150-08.

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ABSTRACT Eukaryotic elongation factor 1 alpha 2 (eEF1A2) is a transforming gene product that is highly expressed in human tumors of the ovary, lung, and breast. eEF1A2 also stimulates actin remodeling, and the expression of this factor is sufficient to induce the formation of filopodia, long cellular processes composed of bundles of parallel actin filaments. Here, we find that eEF1A2 stimulates formation of filopodia by increasing the cellular abundance of cytosolic and plasma membrane-bound phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2]. We have previously reported that the eEF1A2 protein binds and activates phosphatidylinositol-4 kinase III beta (PI4KIIIβ), and we find that production of eEF1A2-dependent PI(4,5)P2 and generation of filopodia require PI4KIIIβ. Furthermore, PI4KIIIβ is itself capable of activating both the production of PI(4,5)P2 and the creation of filopodia. We propose a model for extrusion of filopodia in which eEF1A2 activates PI4KIIIβ, and activated PI4KIIIβ stimulates production of PI(4,5)P2 and filopodia by increasing PI4P abundance. Our work suggests an important role for both eEF1A2 and PI4KIIIβ in the control of PI(4,5)P2 signaling and actin remodeling.
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40

LaMarche, M. J., J. Borawski, A. Bose, C. Capacci-Daniel, R. Colvin, M. Dennehy, J. Ding, et al. "Anti-Hepatitis C Virus Activity and Toxicity of Type III Phosphatidylinositol-4-Kinase Beta Inhibitors." Antimicrobial Agents and Chemotherapy 56, no. 10 (July 23, 2012): 5149–56. http://dx.doi.org/10.1128/aac.00946-12.

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ABSTRACTType III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virusin vitro. Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensivein vitroprofiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.
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Tan, Xiaochao, Priyam Banerjee, Edward A. Pham, Florentine U. N. Rutaganira, Kaustabh Basu, Neus Bota-Rabassedas, Hou-Fu Guo, et al. "PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma." Science Translational Medicine 12, no. 527 (January 22, 2020): eaax3772. http://dx.doi.org/10.1126/scitranslmed.aax3772.

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Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)–dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.
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42

Spickler, Catherine, Julie Lippens, Marie-Kristine Laberge, Sophie Desmeules, Édith Bellavance, Michel Garneau, Tim Guo, et al. "Phosphatidylinositol 4-Kinase III Beta Is Essential for Replication of Human Rhinovirus and Its Inhibition Causes a Lethal PhenotypeIn Vivo." Antimicrobial Agents and Chemotherapy 57, no. 7 (May 6, 2013): 3358–68. http://dx.doi.org/10.1128/aac.00303-13.

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ABSTRACTHuman rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle.In vitroselection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ). A good correlation between PI4KIIIβ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIβ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIβ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIβ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIβ is deleterious.
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43

Larimore, Jennifer, Karine Tornieri, Pearl V. Ryder, Avanti Gokhale, Stephanie A. Zlatic, Branch Craige, Joshua D. Lee, et al. "The schizophrenia susceptibility factor dysbindin and its associated complex sort cargoes from cell bodies to the synapse." Molecular Biology of the Cell 22, no. 24 (December 15, 2011): 4854–67. http://dx.doi.org/10.1091/mbc.e11-07-0592.

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Dysbindin assembles into the biogenesis of lysosome-related organelles complex 1 (BLOC-1), which interacts with the adaptor protein complex 3 (AP-3), mediating a common endosome-trafficking route. Deficiencies in AP-3 and BLOC-1 affect synaptic vesicle composition. However, whether AP-3-BLOC-1–dependent sorting events that control synapse membrane protein content take place in cell bodies upstream of nerve terminals remains unknown. We tested this hypothesis by analyzing the targeting of phosphatidylinositol-4-kinase type II α (PI4KIIα), a membrane protein present in presynaptic and postsynaptic compartments. PI4KIIα copurified with BLOC-1 and AP-3 in neuronal cells. These interactions translated into a decreased PI4KIIα content in the dentate gyrus of dysbindin-null BLOC-1 deficiency and AP-3–null mice. Reduction of PI4KIIα in the dentate reflects a failure to traffic from the cell body. PI4KIIα was targeted to processes in wild-type primary cultured cortical neurons and PC12 cells but failed to reach neurites in cells lacking either AP-3 or BLOC-1. Similarly, disruption of an AP-3–sorting motif in PI4KIIα impaired its sorting into processes of PC12 and primary cultured cortical neuronal cells. Our findings indicate a novel vesicle transport mechanism requiring BLOC-1 and AP-3 complexes for cargo sorting from neuronal cell bodies to neurites and nerve terminals.
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Kang, Min Suk, Seung-Hoon Baek, Yoon Sun Chun, A. Zenobia Moore, Natalie Landman, Diego Berman, Hyun Ok Yang, et al. "Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3." Journal of Biological Chemistry 288, no. 29 (May 30, 2013): 20868–82. http://dx.doi.org/10.1074/jbc.m112.445734.

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Amyloid β-peptide (Aβ) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aβ levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aβ levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aβ-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis.
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45

Judith, Delphine, Harold B. J. Jefferies, Stefan Boeing, David Frith, Ambrosius P. Snijders, and Sharon A. Tooze. "ATG9A shapes the forming autophagosome through Arfaptin 2 and phosphatidylinositol 4-kinase IIIβ." Journal of Cell Biology 218, no. 5 (March 27, 2019): 1634–52. http://dx.doi.org/10.1083/jcb.201901115.

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ATG9A is a multispanning membrane protein essential for autophagy. Normally resident in Golgi membranes and endosomes, during amino acid starvation, ATG9A traffics to sites of autophagosome formation. ATG9A is not incorporated into autophagosomes but is proposed to supply so-far-unidentified proteins and lipids to the autophagosome. To address this function of ATG9A, a quantitative analysis of ATG9A-positive compartments immunoisolated from amino acid–starved cells was performed. These ATG9A vesicles are depleted of Golgi proteins and enriched in BAR-domain containing proteins, Arfaptins, and phosphoinositide-metabolizing enzymes. Arfaptin2 regulates the starvation-dependent distribution of ATG9A vesicles, and these ATG9A vesicles deliver the PI4-kinase, PI4KIIIβ, to the autophagosome initiation site. PI4KIIIβ interacts with ATG9A and ATG13 to control PI4P production at the initiation membrane site and the autophagic response. PI4KIIIβ and PI4P likely function by recruiting the ULK1/2 initiation kinase complex subunit ATG13 to nascent autophagosomes.
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Gerber, Pehuén Pereyra, Mercedes Cabrini, Carolina Jancic, Luciana Paoletti, Claudia Banchio, Catalina von Bilderling, Lorena Sigaut, et al. "Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate." Journal of Cell Biology 209, no. 3 (May 4, 2015): 435–52. http://dx.doi.org/10.1083/jcb.201409082.

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During the late stages of the HIV-1 replication cycle, the viral polyprotein Pr55Gag is recruited to the plasma membrane (PM), where it binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and directs HIV-1 assembly. We show that Rab27a controls the trafficking of late endosomes carrying phosphatidylinositol 4-kinase type 2 α (PI4KIIα) toward the PM of CD4+ T cells. Hence, Rab27a promotes high levels of PM phosphatidylinositol 4-phosphate and the localized production of PI(4,5)P2, therefore controlling Pr55Gag membrane association. Rab27a also controls PI(4,5)P2 levels at the virus-containing compartments of macrophages. By screening Rab27a effectors, we identified that Slp2a, Slp3, and Slac2b are required for the association of Pr55Gag with the PM and that Slp2a cooperates with Rab27a in the recruitment of PI4KIIα to the PM. We conclude that by directing the trafficking of PI4KIIα-positive endosomes toward the PM, Rab27a controls PI(4,5)P2 production and, consequently, HIV-1 replication.
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47

Rajamanoharan, Dayani, Hannah V. McCue, Robert D. Burgoyne, and Lee P. Haynes. "Modulation of phosphatidylinositol 4-phosphate levels by CaBP7 controls cytokinesis in mammalian cells." Molecular Biology of the Cell 26, no. 8 (April 15, 2015): 1428–39. http://dx.doi.org/10.1091/mbc.e14-07-1243.

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Calcium and phosphoinositide signaling regulate cell division in model systems, but their significance in mammalian cells is unclear. Calcium-binding protein-7 (CaBP7) is a phosphatidylinositol 4-kinaseIIIβ (PI4KIIIβ) inhibitor required during cytokinesis in mammalian cells, hinting at a link between these pathways. Here we characterize a novel association of CaBP7 with lysosomes that cluster at the intercellular bridge during cytokinesis in HeLa cells. We show that CaBP7 regulates lysosome clustering and that PI4KIIIβ is essential for normal cytokinesis. CaBP7 depletion induces lysosome mislocalization, extension of intercellular bridge lifetime, and cytokinesis failure. These data connect phosphoinositide and calcium pathways to lysosome localization and normal cytokinesis in mammalian cells.
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48

Sridhar, Sunandini, Bindi Patel, David Aphkhazava, Fernando Macian, Laura Santambrogio, Dennis Shields, and Ana Maria Cuervo. "The lipid kinase PI4KIIIβ preserves lysosomal identity." EMBO Journal 32, no. 3 (December 21, 2012): 324–39. http://dx.doi.org/10.1038/emboj.2012.341.

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49

van der Schaar, Hilde M., Pieter Leyssen, Hendrik J. Thibaut, Armando de Palma, Lonneke van der Linden, Kjerstin H. W. Lanke, Céline Lacroix, et al. "A Novel, Broad-Spectrum Inhibitor of Enterovirus Replication That Targets Host Cell Factor Phosphatidylinositol 4-Kinase IIIβ." Antimicrobial Agents and Chemotherapy 57, no. 10 (July 29, 2013): 4971–81. http://dx.doi.org/10.1128/aac.01175-13.

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ABSTRACTDespite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-a]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in anin vitrokinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-N-(pyridin-4-ylmethyl)imidazo[1,2-a]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model.
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50

WAUGH, Mark G., Shane MINOGUE, Deena BLUMENKRANTZ, J. Simon ANDERSON, and J. Justin HSUAN. "Identification and characterization of differentially active pools of type IIα phosphatidylinositol 4-kinase activity in unstimulated A431 cells." Biochemical Journal 376, no. 2 (December 1, 2003): 497–503. http://dx.doi.org/10.1042/bj20031212.

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The seven known polyphosphoinositides have been implicated in a wide range of regulated and constitutive cell functions, including cell-surface signalling, vesicle trafficking and cytoskeletal reorganization. In order to understand the spatial and temporal control of these diverse cell functions it is necessary to characterize the subcellular distribution of a wide variety of polyphosphoinositide synthesis and signalling events. The predominant phosphatidylinositol kinase activity in many mammalian cell types involves the synthesis of the signalling precursor, phosphatidylinositol 4-phosphate, in a reaction catalysed by the recently cloned PI4KIIα (type IIα phosphatidylinositol 4-kinase). However the regulation of this enzyme and the cellular distribution of its product in different organelles are very poorly understood. This report identifies the existence, in unstimulated cells, of two major subcellular membrane fractions, which contain PI4KIIα possessing different levels of intrinsic activity. Separation of these membranes from each other and from contaminating activities was achieved by density gradient ultracentrifugation at pH 11 in a specific detergent mixture in which both membrane fractions, but not other membranes, were insoluble. Kinetic comparison of the purified membrane fractions revealed a 4-fold difference in Km for phosphatidylinositol and a 3.5-fold difference in Vmax, thereby indicating a different mechanism of regulation to that described previously for agonist-stimulated cells. These marked differences in basal activity and the occurrence of this isozyme in multiple organelles emphasize the need to investigate cell signalling via PI4KIIα at the level of individual organelles rather than whole-cell lysates.
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