Lipid phosphate phosphatase 3 participates in transport carrier formation and protein trafficking in the early secretory pathway

Gutiérrez-Martínez, Enric; Fernández-Ulibarri, Inés; Lázaro‐Diéguez, Francisco; Johannes, Ludger; Pyne, Susan; Sarri, Elisabet; Egea, Gustavo

doi:10.1242/jcs.117705

Cited by 34 publications

(39 citation statements)

References 78 publications

(89 reference statements)

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“…Overexpression of LPP3 in Swiss 3T3 and HEK293 cells increases the conversion of PA to DG ( 90 ). LPP3 depletion decreases the levels of de novo synthesized DG and the Golgi-associated DG content, which impairs protein traffi cking in the early secretory pathway ( 91 ). Furthermore, LPP2 and LPP3 decrease cell survival by regulating the intracellular levels of PA ( 92 ).…”

Section: The Role Of Lpps In Pathologymentioning

confidence: 99%

Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

Tang

Benesch

Brindley

2015

Journal of Lipid Research

129

130

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Section: The Role Of Lpps In Pathologymentioning

confidence: 99%

Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

Tang

Benesch

Brindley

2015

Journal of Lipid Research

129

130

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“…Immunofluorescence Microscopy-HeLa cells were fixed and processed as described previously (53). Working dilutions of antibodies were as follows: anti-GM130 (1:1000); anti-Golgin97 (1:300); anti-TGN46 (1:500).…”

Section: ϫ05mentioning

confidence: 99%

Actin Filaments Are Involved in the Coupling of V0-V1 Domains of Vacuolar H+-ATPase at the Golgi Complex

Serra‐Peinado¹,

Sicart²,

Llopis³

et al. 2016

Journal of Biological Chemistry

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We previously reported that actin-depolymerizing agents promote the alkalization of the Golgi stack and the trans-Golgi network. The main determinant of acidic pH at the Golgi is the vacuolar-type H ؉ -translocating ATPase (V-ATPase), whose V 1 domain subunits B and C bind actin. We have generated a GFPtagged subunit B2 construct (GFP-B2) that is incorporated into the V 1 domain, which in turn is coupled to the V 0 sector. GFP-B2 subunit is enriched at distal Golgi compartments in HeLa cells. Subcellular fractionation, immunoprecipitation, and inversal FRAP experiments show that the actin depolymerization promotes the dissociation of V 1 -V 0 domains, which entails subunit B2 translocation from Golgi membranes to the cytosol. Moreover, molecular interaction between subunits B2 and C1 and actin were detected. In addition, Golgi membrane lipid order disruption by D-ceramide-C6 causes Golgi pH alkalization. We conclude that actin regulates the Golgi pH homeostasis maintaining the coupling of V 1 -V 0 domains of V-ATPase through the binding of microfilaments to subunits B and C and preserving the integrity of detergent-resistant membrane organization. These results establish the Golgi-associated V-ATPase activity as the molecular link between actin and the Golgi pH.The secretory pathway is characterized by progressive lumen acidification of its organelles, from almost neutral in the endoplasmic reticulum (ER) 4 (pH Ϸ7.1-7.2), along the cis-to-trans Golgi stack (pH Ϸ6.7-6.0), to more acidic in the trans-Golgi network (TGN) and secretory vesicles/granules (pH Ϸ5.0) (1-3). This pH gradient is crucial for post-translational modifications and membrane trafficking events (4, 5). The main molecular determinant of the progressive fall in pH along the secretory pathway is the vacuolar [H ϩ ]ATPase (V-ATPase) (6 -8). V-ATPase is a multisubunit complex composed of two large domains, V 0 and V 1 . The V 0 domain is a 260-kDa integral membrane complex made up of five different subunits (a, b, c, cЈ, cЉ, d, and e), which mediates proton translocation; the V 1 domain is a 600 -650-kDa peripheral complex composed of eight different subunits (A, B, C, D, E, F, G, and H), which is responsible for the ATP hydrolysis that provides the mechanical force necessary for proton (H ϩ ) translocation (7, 9 -11). Whereas they are the primary source of proton delivery to endomembranes consuming ATP, the final steady-state pH in the secretory pathway is the result of the balance between active H ϩ pumping by the V-ATPase, passive H ϩ efflux through organelle endogenous H ϩ permeability, and differences in counter-ion conductance (3, 12).How differences in the pH of individual secretory compartments are generated is not well understood. Differential VATPase density and/or local regulatory mechanisms in secretory organelles and subcompartments are possible (13). In this respect, V-ATPase-dependent proton translocation could be regulated by several mechanisms, which include the following: (a) differential V-ATPase subunit expression; (b) intracel...

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“…These include pathways mediated by the Raf and mTOR protein kinases and conventional protein kinases C ( 13 , 14 ). Evidence that LPP3 has an intracellular role as a regulator of vesicular transport between the endoplasmic reticulum and Golgi apparatus has also been reported ( 15 ). It is also important to note that not all studies of the effects of LPP overexpression have revealed phenotypes in cell and animals that can be explained simply by attenuation of LPA signaling ( 16 ).…”

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confidence: 98%

Lipid phosphate phosphatases: more than one way to put the brakes on LPA signaling?

Morris

Smyth

2014

Journal of Lipid Research

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Journal of Lipid Research Volume 55, 2014 2195Lipid phosphate phosphatases (LPPs, encoded by the PPAP2 genes) are broad specifi city enzymes that can dephosphorylate lipid phosphate esters such as phosphatidic acid (PA), lysophosphatidic acid (LPA), and sphingosine-1-phosphate (S1P) that serve as critical intermediates in intracellular pathways of lipid metabolism and signaling ( Fig. 1 ) ( 1 ). Of these substrates, LPA and S1P are also bioactive mediators that can be released or generated extracellularly and/or act on cell surface receptors to initiate a broad range of cellular responses ( 2 ). LPPs can localize to the cell surface with their active site facing the extracellular space allowing them to function as ecto enzymes ( 3 , 4 ). Accordingly, it has been attractive to speculate that one function of these enzymes is to terminate the receptormediated signaling actions of LPA and S1P by dephosphorylating them to generate the corresponding alcohols, which are not receptor-active. In support of this concept, overexpression of LPP1 or LPP3 increases the LPP activity of several intact cells, and this activity is decreased by silencing or genetic inactivation of the corresponding PPAP2A and PPAP2B genes ( 5 -7 ). These manipulations are broadly associated with reciprocal effects on LPA responsiveness of stereotypic cellular responses to this stimulus, particularly cell growth and migration. Mice that are genetically hypomorphic for the PPAP2A gene encoding LPP1 exhibit increased circulating LPA levels ( 8 ) whereas inducible postnatal and/or tissue-restricted inactivation of the PPAP2B gene encoding LPP3 alters S1P gradients that control lymphocyte egress from the lymphatic system to the peripheral circulation ( 9 ) and renders vascular smooth muscle cells more responsive to LPA ( 6 ).In Drosophila , LPP homologs encoded by the Wunen genes regulate the migration of germ cells in the developing embryo ( 10 ). Ectopic expression of these genes in somatic tissues that are normally permissive for germ cell migration results in repulsion of the migrating germ cells. This nonautonomous function of the Wunen genes is consistent with the idea that a diffusible Wunen substrate regulates germ cell migration ( 11 ). However, Wunens are also expressed in the germ cells themselves from maternally inherited mRNA and inactivation of Wunen in the female germline also decreases germ cell migration identifying a cell autonomous function for these genes ( 12 ).LPPs also localize to intracellular membranes. Manipulations of LPP expression have also been shown to alter levels of cell-associated LPP substrates and products including PA and its dephosphorylation product diacylglycerol (DG) that are well established to regulate intracellular signaling pathways. These include pathways mediated by the Raf and mTOR protein kinases and conventional protein kinases C ( 13 , 14 ). Evidence that LPP3 has an intracellular role as a regulator of vesicular transport between the endoplasmic reticulum and Golgi apparatus has also been reported ( 1...

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Lipid phosphate phosphatase 3 participates in transport carrier formation and protein trafficking in the early secretory pathway

Cited by 34 publications

References 78 publications

Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

Actin Filaments Are Involved in the Coupling of V0-V1 Domains of Vacuolar H+-ATPase at the Golgi Complex

Lipid phosphate phosphatases: more than one way to put the brakes on LPA signaling?

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