VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast and mouse

Jin, Natsuko; Chow, Clement Y.; Liu, Li; Zolov, Sergey N.; Bronson, Roderick; Davisson, Muriel T.; Petersen, Jason L.; Zhang, Yanling; Park, Su‐Jin; Duex, Jason E.; Goldowitz, Dan; Meisler, Miriam H.; Weisman, Lois S.

doi:10.1038/emboj.2008.248

Cited by 225 publications

(344 citation statements)

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“…The importance of PtdIns(3,5)P 2 production in vivo has been demonstrated by genetic disruption of Vac14 and Fig4 in mice, which in both cases results in premature death and profound degeneration of the nervous system (8,12,13). The results of our study show that PIPKIII is essential for the homeostasis of a nonneuronal mammalian tissue, the murine adult intestinal epithelium.…”

Section: Discussionmentioning

confidence: 48%

“…TEA-stimulated increase of PtdIns (3,5)P 2 was absent in ES cells lacking PIPKIII. These results demonstrate that, as is true for Fab1p in yeast, PIPKIII is the major PtdIns(3,5)P 2 -producing kinase in mammalian cells, and that disruption of PipkIII leads to a more profound decrease in cellular PtdIns(3,5)P 2 levels than does disruption of either Vac14 or Fig4 (8,12,13).…”

Section: Resultsmentioning

confidence: 61%

“…To investigate the physiological roles of PIPKIII in a whole mammal, we generated PipkIII neo/+ mice and intercrossed them to generate PipkIII neo/neo progeny. In contrast to Vac14-and Fig4-deficient mice (8,12,13), loss of the PipkIII gene was lethal during early embryogenesis (Table 1). Mendelian analysis showed that PipkIII neo/neo embryos were present at close to the expected frequency at embryonic day (E)6.5 and E7.5 but were visibly abnormal (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, given the plethora of roles proposed for endosomal structures in mammalian cells, PIPKIII-mediated production of PtdIns(3,5)P 2 is likely to be involved in numerous complex physiological processes in mammals. This hypothesis has been bolstered by analyses of the phenotypes of mice with germ-line mutations of Vac14 or Fig4 (8,12,13). Mice lacking either Vac14 or Fig4 are born but exhibit severe neuronal damage and have a shortened lifespan.…”

mentioning

confidence: 99%

“…The chaperonin-like and cysteine-rich domains of Fab1p are involved in its binding to Vac14p and Fig4p, which are two regulatory proteins required for Fab1p's full kinase activity. Vac14 and Fig4 are conserved in mammals, participate in a trimeric complex with PIPKIII, and are thought to have a similar function in promoting full PIPKIII kinase activity (8,9).…”

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confidence: 99%

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Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine

Takasuga

Horie²,

Sasaki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The metabolism of membrane phosphoinositides is critical for a variety of cellular processes. 5)P 2 ] controls multiple steps of the intracellular membrane trafficking system in both yeast and mammalian cells. However, other than in neuronal tissues, little is known about the physiological functions of PtdIns(3,5)P 2 in mammals. Here, we provide genetic evidence that type III phosphatidylinositol phosphate kinase (PIPKIII), which produces PtdIns(3,5)P 2 , is essential for the functions of polarized epithelial cells. PIPKIII-null mouse embryos die by embryonic day 8.5 because of a failure of the visceral endoderm to supply the epiblast with maternal nutrients. Similarly, although intestine-specific PIPKIII-deficient mice are born, they fail to thrive and eventually die of malnutrition. At the mechanistic level, we show that PIPKIII regulates the trafficking of proteins to a cell's apical membrane domain. Importantly, mice with intestine-specific deletion of PIPKIII exhibit diarrhea and bloody stool, and their gut epithelial layers show inflammation and fibrosis, making our mutants an improved model for inflammatory bowel diseases. In summary, our data demonstrate that PIPKIII is required for the structural and functional integrity of two different types of polarized epithelial cells and suggest that PtdIns(3,5)P 2 metabolism is an unexpected and critical link between membrane trafficking in intestinal epithelial cells and the pathogenesis of inflammatory bowel disease.embryogenesis | Crohn's disease

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Section: Discussionmentioning

confidence: 48%

Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine

Takasuga

Horie²,

Sasaki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Phosphoinositide‐binding proteins in autophagy

Lystad

Simonsen

2016

FEBS Letters

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Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

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Neuropathology of childhood‐onset basal ganglia degeneration caused by mutation of VAC14

Stutterd

Diakumis

Bahlo

et al. 2017

Ann Clin Transl Neurol

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Objective: To characterize the clinical features and neuropathology associated with recessive VAC14 mutations. Methods: Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressive neurological disease presenting in early childhood in two deceased siblings with distinct neuropathological features on post mortem examination. Results: We identified compound heterozygous variants in VAC14 in two deceased siblings with early childhood onset of severe, progressive dystonia, and neurodegeneration. Their clinical phenotype is consistent with the VAC14-related childhood-onset, striatonigral degeneration recently described in two unrelated children. Post mortem examination demonstrated prominent vacuolation associated with degenerating neurons in the caudate nucleus, putamen, and globus pallidus, similar to previously reported ex vivo vacuoles seen in the late-endosome/lysosome of VAC14-deficient neurons. We identified upregulation of ubiquitinated granules within the cell cytoplasm and lysosomal-associated membrane protein (LAMP2) around the vacuole edge to suggest a process of vacuolation of lysosomal structures associated with active autophagocytic-associated neuronal degeneration. Interpretation: Our findings reveal a distinct clinicopathological phenotype associated with recessive VAC14 mutations.

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VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast and mouse

Cited by 225 publications

References 31 publications

Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine

Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine

Phosphoinositide‐binding proteins in autophagy

Neuropathology of childhood‐onset basal ganglia degeneration caused by mutation of VAC14

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