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Thomas Langer - One of the best experts on this subject based on the ideXlab platform.
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disturbed intramitochondrial Phosphatidic Acid transport impairs cellular stress signaling
Journal of Biological Chemistry, 2021Co-Authors: Akinori Eiyama, Takashi Tatsuta, Mari J Aaltonen, Thomas Langer, Hendrik NolteAbstract:Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle Phosphatidic Acid (PA) mainly synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the CL synthase Crd1, Ups1-deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1Δ cells leads to altered unfolded protein response (UPR) and mTORC1 signaling, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine and a reduced phosphatidylethanolamine/phosphatidylcholine ratio in the ER of ups1Δ cells which suppresses the UPR. Moreover, we observed inhibition of target of rapamycin complex 1 (TORC1) signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the Seh1-associated complex inhibiting TORC1 complex, increased cytosolic protein synthesis, and restored glycolytic growth of ups1Δ cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
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Disturbed intramitochondrial Phosphatidic Acid transport impairs cellular stress signaling
2020Co-Authors: Akinori Eiyama, Takashi Tatsuta, Mari J Aaltonen, Hendrik Nolte, Thomas LangerAbstract:Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle Phosphatidic Acid (PA) synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the cardiolipin synthase Crd1, Ups1 deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1{Delta} cells leads to altered phospholipid composition of the ER membrane, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine (PC) and a reduced phosphatidylethanolamine (PE)/PC ratio in the ER of ups1{Delta} cells which suppresses the unfolded protein response (UPR). Moreover, we observed inhibition of TORC1 signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the SEACIT complex, increased cytosolic protein synthesis and restored glycolytic growth of ups1{Delta} cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.
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triap1 preli complexes prevent apoptosis by mediating intramitochondrial transport of Phosphatidic Acid
Cell Metabolism, 2013Co-Authors: Christoph Potting, Mathias Haag, Takashi Tatsuta, Tim Konig, Timothy Wai, Mari J Aaltonen, Thomas LangerAbstract:Summary Cardiolipin (CL), a mitochondria-specific glycerophospholipid, is required for diverse mitochondrial processes and orchestrates the function of various death-inducing proteins during apoptosis. Here, we identify a complex of the p53-regulated protein TRIAP1 (p53CSV) and PRELI in the mitochondrial intermembrane space (IMS), which ensures the accumulation of CL in mitochondria. TRIAP1/PRELI complexes exert lipid transfer activity in vitro and supply Phosphatidic Acid (PA) for CL synthesis in the inner membrane. Loss of TRIAP1 or PRELI impairs the accumulation of CL, facilitates the release of cytochrome c , and renders cells vulnerable to apoptosis upon intrinsic and extrinsic stimulation. Survival of TRIAP1- and PRELI-deficient cells is conferred by an excess of exogenously provided phosphatidylglycerol. Our results reveal a p53-dependent cell-survival pathway and highlight the importance of the CL content of mitochondrial membranes in apoptosis.
Xuemin Wang - One of the best experts on this subject based on the ideXlab platform.
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phospholipase d and Phosphatidic Acid mediated phospholipid metabolism and signaling modulate symbiotic interaction and nodulation in soybean glycine max
Plant Journal, 2021Co-Authors: Gaoyang Zhang, Xuemin Wang, Jihong Yang, Xiangli Chen, Dandan Zhao, Xiuhong Zhou, Yuliang Zhang, Jian ZhaoAbstract:Symbiotic rhizobium-legume interactions, such as root hair curling, rhizobial invasion, infection thread expansion, cell division and proliferation of nitrogen-fixing bacteroids, and nodule formation, involve extensive membrane synthesis, lipid remodeling and cytoskeleton dynamics. However, little is known about these membrane-cytoskeleton interfaces and related genes. Here, we report the roles of a major root phospholipase D (PLD), PLDα1, and its enzymatic product, Phosphatidic Acid (PA), in rhizobium-root interaction and nodulation. PLDα1 was activated and the PA content transiently increased in roots after rhizobial infection. Levels of PLDα1 transcript and PA, as well as actin and tubulin cytoskeleton-related gene expression, changed markedly during root-rhizobium interactions and nodule development. Pre-treatment of the roots of soybean seedlings with n-butanol suppressed the generation of PLD-derived PA, the expression of early nodulation genes and nodule numbers. Overexpression or knockdown of GmPLDα1 resulted in changes in PA levels, glycerolipid profiles, nodule numbers, actin cytoskeleton dynamics, early nodulation gene expression and hormone levels upon rhizobial infection compared with GUS roots. The transcript levels of cytoskeleton-related genes, such as GmACTIN, GmTUBULIN, actin capping protein 1 (GmCP1) and microtubule-associating protein (GmMAP1), were modified in GmPLDα1-altered hairy roots compared with those of GUS roots. Phosphatidic Acid physically bound to GmCP1 and GmMAP1, which could be related to cytoskeletal changes in rhizobium-infected GmPLDα1 mutant roots. These data suggest that PLDα1 and PA play important roles in soybean-rhizobium interaction and nodulation. The possible underlying mechanisms, including PLDα1- and PA-mediated lipid signaling, membrane remodeling, cytoskeleton dynamics and related hormone signaling, are discussed herein.
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phospholipase d and Phosphatidic Acid signalling in plant response to drought and salinity
Plant Cell and Environment, 2010Co-Authors: Yueyun Hong, Wenhua Zhang, Xuemin WangAbstract:: The activity of phospholipase D (PLD) in plants increases under different hyperosmotic stresses, such as dehydration, drought, and salinity. Recent results begin to shed light onto the involvement of PLD in response to water deficits and salinity. Different PLDs have unique and overlapping functions in these responses. PLDalpha1 promotes stomatal closure and reduces water loss. PLDalpha1 and PLDdelta are involved in seedling tolerance to salt stress. PLDalpha3 and PLDepsilon enhance plant growth and hyperosmotic tolerance. The different PLDs regulate the production of Phosphatidic Acid (PA) that is a key class of lipid mediators in plant response to environmental stresses. Further studies on the upstream regulators that activate different PLDs and the downstream effectors of PLDs and PA have the potential to unveil the linkage between the stimulus perception at the cell membrane to intracellular responses to drought and salinity stresses.
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phospholipase d and Phosphatidic Acid mediated signaling in plants
Biochimica et Biophysica Acta, 2009Co-Authors: Maoyin Li, Xuemin Wang, Yueyun HongAbstract:The phospholipase D (PLD) family in higher plants is composed of multiple members, and each of the Arabidopsis PLDs characterized displays distinguishable properties in activity regulation and/or lipid preferences. The molecular and biochemical heterogeneities of the plant PLDs play important roles in the timing, location, and amount of Phosphatidic Acid (PA) produced. PLD-catalyzed production of PA has been shown to play important roles in plant growth, development, and response to various stresses, including drought, salinity, freezing, and nutrient deficiency. PLD and PA affect cellular processes through different modes of action, including direct target protein binding and biophysical effects on cell membranes. Improved knowledge on the mechanism by which specific PLDs and PA mediate given plant responses will facilitate the understanding of the molecular processes that connect the stimulus perception on membranes to intracellular actions and physiological responses.
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regulatory functions of phospholipase d and Phosphatidic Acid in plant growth development and stress responses
Plant Physiology, 2005Co-Authors: Xuemin WangAbstract:Phospholipase D (PLD) hydrolyzes membrane lipids to generate Phosphatidic Acid (PA) and a free-head group ([Fig. 1][1]), and this activity is widespread in plants. Recent results indicate that PLD plays multiple regulatory roles in diverse plant processes, including abscisic Acid (ABA) signaling,
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phospholipase d and Phosphatidic Acid mediated generation of superoxide in arabidopsis
Plant Physiology, 2001Co-Authors: Yongming Sang, Xuemin WangAbstract:Phospholipase D (PLD), which hydrolyzes phospholipids into free head groups and Phosphatidic Acid (PA), may regulate cellular processes through the production of lipid and lipid-derived messengers. We have genetically abrogated PLDα, the most prevalent isoform of PLD in plants, and the depletion of PLDα in Arabidopsis decreased the levels of PA and superoxide production in Arabidopsis leaf extracts. Addition of PA promoted the synthesis of superoxide in the PLDα-depleted plants, as measured by chemiluminescence and superoxide dismutase-inhibitable, NADPH-dependent reduction of cytochrome c and nitroblue tetrazolium. The PA-enhanced generation of superoxide was associated mainly with microsomal membranes. Among various lipids tested, PA was the most effective stimulator with the optimal concentrations between 100 and 200 μm. The PA-promoted production of superoxide was observed also in leaves directly infiltrated with PA. The added PA was more effective in stimulating superoxide generation in the PLDα-depleted leaves than in the PLDα-containing, wild-type leaves, suggesting that PA produced in the cell was more effective than added PA in promoting superoxide production. These data indicate that PLD plays a role in mediating superoxide production in plants through the generation of PA as a lipid messenger.
Meesup Yoon - One of the best experts on this subject based on the ideXlab platform.
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rapid mitogenic regulation of the mtorc1 inhibitor deptor by Phosphatidic Acid
Molecular Cell, 2015Co-Authors: Christina L Rosenberger, Meesup Yoon, Nga Truong, Jonathan V. Sweedler, Cong Wu, Jie ChenAbstract:The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product Phosphatidic Acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty Acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a novel mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.
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rapid mitogenic regulation of the mtorc1 inhibitor deptor by Phosphatidic Acid
Molecular Cell, 2015Co-Authors: Christina L Rosenberger, Meesup Yoon, Nga Truong, Jonathan V. Sweedler, Cong Wu, Jie ChenAbstract:The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product Phosphatidic Acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty Acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a novel mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.
Jie Chen - One of the best experts on this subject based on the ideXlab platform.
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rapid mitogenic regulation of the mtorc1 inhibitor deptor by Phosphatidic Acid
Molecular Cell, 2015Co-Authors: Christina L Rosenberger, Meesup Yoon, Nga Truong, Jonathan V. Sweedler, Cong Wu, Jie ChenAbstract:The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product Phosphatidic Acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty Acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a novel mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.
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rapid mitogenic regulation of the mtorc1 inhibitor deptor by Phosphatidic Acid
Molecular Cell, 2015Co-Authors: Christina L Rosenberger, Meesup Yoon, Nga Truong, Jonathan V. Sweedler, Cong Wu, Jie ChenAbstract:The mammalian target of rapamycin complex 1 (mTORC1) is regulated, in part, by the endogenous inhibitor DEPTOR. However, the mechanism of DEPTOR regulation with regard to rapid mTORC1 activation remains unknown. We report that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation, suggesting a mechanism underlying acute mTORC1 activation. This mitogen-stimulated DEPTOR dissociation is blocked by inhibition or depletion of the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product Phosphatidic Acid (PA). Our mass spectrometry analysis has independently identified DEPTOR as an mTOR binding partner dissociated by PA. Interestingly, only PA species with unsaturated fatty Acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. Our findings reveal a novel mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.
Michael A Frohman - One of the best experts on this subject based on the ideXlab platform.
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Phosphatidic Acid pa preferring phospholipase a1 regulates mitochondrial dynamics
Journal of Biological Chemistry, 2014Co-Authors: Takashi Baba, Takeshi Kogure, Yuriko Kashiwagi, Nagisa Arimitsu, Ayumi Edo, Tomohiro Maruyama, Kazuki Nakao, Hiroki Nakanishi, Makoto Kinoshita, Michael A FrohmanAbstract:Recent studies have suggested that Phosphatidic Acid (PA), a cone-shaped phospholipid that can generate negative curvature of lipid membranes, participates in mitochondrial fusion. However, precise mechanisms underling the production and consumption of PA on the mitochondrial surface are not fully understood. Phosphatidic Acid-preferring phospholipase A1 (PA-PLA1)/DDHD1 is the first identified intracellular phospholipase A1 and preferentially hydrolyzes PA in vitro. Its cellular and physiological functions have not been elucidated. In this study, we show that PA-PLA1 regulates mitochondrial dynamics. PA-PLA1, when ectopically expressed in HeLa cells, induced mitochondrial fragmentation, whereas its depletion caused mitochondrial elongation. The effects of PA-PLA1 on mitochondrial morphology appear to counteract those of MitoPLD, a mitochondrion-localized phospholipase D that produces PA from cardiolipin. Consistent with high levels of expression of PA-PLA1 in testis, PA-PLA1 knock-out mice have a defect in sperm formation. In PA-PLA1-deficient sperm, the mitochondrial structure is disorganized, and an abnormal gap structure exists between the middle and principal pieces. A flagellum is bent at that position, leading to a loss of motility. Our results suggest a possible mechanism of PA regulation of the mitochondrial membrane and demonstrate an in vivo function of PA-PLA1 in the organization of mitochondria during spermiogenesis. Background: Phosphatidic Acid (PA) is involved in membrane dynamics. Results: PA-preferring phospholipase A1 (PA-PLA1) affects mitochondrial morphology in an activity-dependent manner. Gene disruption of PA-PLA1 in mice causes sperm malformation due to mitochondrial organization defects. Conclusion: PA-PLA1 regulates mitochondrial dynamics. Significance: We demonstrate an in vivo function of PA-PLA1 and suggest a possible mechanism of PA regulation of the mitochondrial membrane.
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Phosphatidic Acid pa preferring phospholipase a1 regulates mitochondrial dynamics
Journal of Biological Chemistry, 2014Co-Authors: Takashi Baba, Takeshi Kogure, Yuriko Kashiwagi, Nagisa Arimitsu, Ayumi Edo, Tomohiro Maruyama, Kazuki Nakao, Hiroki Nakanishi, Makoto Kinoshita, Michael A FrohmanAbstract:Recent studies have suggested that Phosphatidic Acid (PA), a cone-shaped phospholipid that can generate negative curvature of lipid membranes, participates in mitochondrial fusion. However, precise mechanisms underling the production and consumption of PA on the mitochondrial surface are not fully understood. Phosphatidic Acid-preferring phospholipase A1 (PA-PLA1)/DDHD1 is the first identified intracellular phospholipase A1 and preferentially hydrolyzes PA in vitro. Its cellular and physiological functions have not been elucidated. In this study, we show that PA-PLA1 regulates mitochondrial dynamics. PA-PLA1, when ectopically expressed in HeLa cells, induced mitochondrial fragmentation, whereas its depletion caused mitochondrial elongation. The effects of PA-PLA1 on mitochondrial morphology appear to counteract those of MitoPLD, a mitochondrion-localized phospholipase D that produces PA from cardiolipin. Consistent with high levels of expression of PA-PLA1 in testis, PA-PLA1 knock-out mice have a defect in sperm formation. In PA-PLA1-deficient sperm, the mitochondrial structure is disorganized, and an abnormal gap structure exists between the middle and principal pieces. A flagellum is bent at that position, leading to a loss of motility. Our results suggest a possible mechanism of PA regulation of the mitochondrial membrane and demonstrate an in vivo function of PA-PLA1 in the organization of mitochondria during spermiogenesis.
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phospholipase d2 dependent inhibition of the nuclear hormone receptor pparγ by cyclic Phosphatidic Acid
Molecular Cell, 2010Co-Authors: Tamotsu Tsukahara, Ryoko Tsukahara, Alyssa L Bolen, Guangwei Du, Fabio Re, Louisa Balazs, Chunxiang Zhang, Yuko Fujiwara, Yunhui Cheng, Michael A FrohmanAbstract:Summary Cyclic Phosphatidic Acid (1-acyl-2,3-cyclic-glycerophosphate, CPA), one of nature's simplest phospholipids, is found in cells from slime mold to humans and has a largely unknown function. We find here that CPA is generated in mammalian cells in a stimulus-coupled manner by phospholipase D2 (PLD2) and binds to and inhibits the nuclear hormone receptor PPARγ with nanomolar affinity and high specificity through stabilizing its interaction with the corepressor SMRT. CPA production inhibits the PPARγ target-gene transcription that normally drives adipocytic differentiation of 3T3-L1 cells, lipid accumulation in RAW264.7 cells and primary mouse macrophages, and arterial wall remodeling in a rat model in vivo. Inhibition of PLD2 by shRNA, a dominant-negative mutant, or a small molecule inhibitor blocks CPA production and relieves PPARγ inhibition. We conclude that CPA is a second messenger and a physiological inhibitor of PPARγ, revealing that PPARγ is regulated by endogenous agonists as well as by antagonists.
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Phospholipase D2-generated Phosphatidic Acid couples EGFR stimulation to Ras activation by Sos
Nature cell biology, 2007Co-Authors: Chen Zhao, Michael A Frohman, Karl Skowronek, Dafna Bar-sagiAbstract:The activation of Ras by the guanine nucleotide-exchange factor Son of sevenless (Sos) constitutes the rate-limiting step in the transduction process that links receptor tyrosine kinases to Ras-triggered intracellular signalling pathways. A prerequisite for the function of Sos in this context is its ligand-dependent membrane recruitment, and the prevailing model implicates both the Sos carboxy-terminal proline-rich motifs and amino-terminal pleckstrin homology (PH) domain in this process. Here, we describe a previously unrecognized pathway for the PH domain-dependent membrane recruitment of Sos that is initiated by the growth factor-induced generation of Phosphatidic Acid via the signalling enzyme phospholipase D2 (PLD2). Phosphatidic Acid interacts with a defined site in the Sos PH domain with high affinity and specificity. This interaction is essential for epidermal growth factor (EGF)-induced Sos membrane recruitment and Ras activation. Our findings establish a crucial role for PLD2 in the coupling of extracellular signals to Sos-mediated Ras activation, and provide new insights into the spatial coordination of this activation event.
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dynamics and function of phospholipase d and Phosphatidic Acid during phagocytosis
Traffic, 2006Co-Authors: Matthias Corrotte, Guangwei Du, Mariefrance Bader, Sylvette Chasserotgolaz, Michael A Frohman, Nicolas Vitale, Nicholas T Ktistakis, Ping Huang, Nancy J. GrantAbstract:Phospholipase D (PLD) produces Phosphatidic Acid (PA), an established intracellular signalling lipid that has been also implicated in vesicular trafficking, and as such, PLD could play multiple roles during phagocytosis. Using an RNA interference strategy, we show that endogenous PLD1 and PLD2 are necessary for efficient phagocytosis in murine macrophages, in line with results obtained with wild-type constructs and catalytically inactive PLD mutants which, respectively, enhance and inhibit phagocytosis. Furthermore, we found that PA is transiently produced at sites of phagosome formation. Macrophage PLD1 and PLD2 differ in their subcellular distributions. PLD1 is associated with cytoplasmic vesicles, identified as a late endosomal/lysosomal compartment, whereas PLD2 localizes at the plasma membrane. In living cells undergoing phagocytosis, PLD1 vesicles are recruited to nascent and internalized phagosomes, whereas PLD2 is only observed on nascent phagosomes. These results provide evidence that both PLD isoforms are required for phagosome formation, but only PLD1 seems to be implicated in later stages of phagocytosis occurring after phagosomal internalization.
