title: Phosphatidylinositol 4-phosphate and phosphatidylinositol 3-phosphate regulate phagolysosome biogenesis.
abstract: Professional phagocytic cells ingest microbial intruders by engulfing them into phagosomes, which subsequently mature into microbicidal phagolysosomes. Phagosome maturation requires sequential fusion of the phagosome with early endosomes, late endosomes, and lysosomes. Although various phosphoinositides (PIPs) have been detected on phagosomes, it remained unclear which PIPs actually govern phagosome maturation. Here, we analyzed the involvement of PIPs in fusion of phagosomes with various endocytic compartments and identified phosphatidylinositol 4-phosphate [PI(4)P], phosphatidylinositol 3-phosphate [PI(3)P], and the lipid kinases that generate these PIPs, as mediators of phagosome-lysosome fusion. Phagosome-early endosome fusion required PI(3)P, yet did not depend on PI(4)P. Thus, PI(3)P regulates phagosome maturation at early and late stages, whereas PI(4)P is selectively required late in the pathway.
authors.affiliation: Cell Biology Institute, University of Bonn, 53121 Bonn, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeschke
authors.affiliation: Division of Immunochemistry, Department of Molecular Infection Biology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany;
authors.forename: Nicole
authors.initials: N
authors.lastname: Zehethofer
authors.affiliation: Division of Immunochemistry, Department of Molecular Infection Biology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany;
authors.forename: Buko
authors.initials: B
authors.lastname: Lindner
authors.affiliation: Cell Biology Institute, University of Bonn, 53121 Bonn, Germany;
authors.forename: Jessica
authors.initials: J
authors.lastname: Krupp
authors.affiliation: Division of Immunochemistry, Department of Molecular Infection Biology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany;
authors.forename: Dominik
authors.initials: D
authors.lastname: Schwudke
authors.affiliation: Department of Medicine, Max von Pettenkofer-Institute, Ludwig-Maximilians University Munich, 80336 Munich, Germany; Institute of Medical Microbiology, University of Zurich, 8006 Zurich, Switzerland;
authors.forename: Ina
authors.initials: I
authors.lastname: Haneburger
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Marko
authors.initials: M
authors.lastname: Jovic
authors.affiliation: Molecular Pharmacology, Belfer Institute for Advanced Biomedical Sciences, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.affiliation: Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Tamas
authors.initials: T
authors.lastname: Balla
authors.affiliation: Department of Medicine, Max von Pettenkofer-Institute, Ludwig-Maximilians University Munich, 80336 Munich, Germany; Institute of Medical Microbiology, University of Zurich, 8006 Zurich, Switzerland;
authors.forename: Hubert
authors.initials: H
authors.lastname: Hilbi
authors.affiliation: Cell Biology Institute, University of Bonn, 53121 Bonn, Germany; albert.haas@uni-bonn.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Haas
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002474:Cell-Free System / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D011992:Endosomes / Q000378:metabolism; D015151:Immunoblotting; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D013058:Mass Spectrometry; D008561:Membrane Fusion; D051379:Mice; D008856:Microscopy, Fluorescence; D008863:Microspheres; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*
chemical_list: D018129:Phosphatidylinositol Phosphates; C055525:phosphatidylinositol 3-phosphate; C037178:phosphatidylinositol 4-phosphate; D019869:Phosphatidylinositol 3-Kinases; D019870:1-Phosphatidylinositol 4-Kinase
keywords: Legionella pneumophila; cell-free membrane fusion; lysosome; phagosome; phosphoinositides
references.citation: J Cell Sci. 2006 Apr 1;119(Pt 7):1219-32
references.pmid: 16522686
references.citation: EMBO J. 2006 Apr 19;25(8):1579-89
references.pmid: 16601699
references.citation: Nature. 2006 Oct 12;443(7112):651-7
references.pmid: 17035995
references.citation: EMBO J. 2007 Jan 24;26(2):313-24
references.pmid: 17245426
references.citation: Traffic. 2007 Apr;8(4):311-30
references.pmid: 17274798
references.citation: Cell Microbiol. 2007 Oct;9(10):2381-90
references.pmid: 17555516
references.citation: Traffic. 2007 Oct;8(10):1365-74
references.pmid: 17645435
references.citation: Mol Biol Cell. 2008 Apr;19(4):1415-26
references.pmid: 18256276
references.citation: J Cell Sci. 2008 Jun 15;121(Pt 12):1955-63
references.pmid: 18525025
references.citation: Mol Biol Cell. 2008 Aug;19(8):3334-46
references.pmid: 18524850
references.citation: EMBO J. 2008 Oct 8;27(19):2457-70
references.pmid: 18784754
references.citation: Cell Microbiol. 2008 Dec;10(12):2416-33
references.pmid: 18673369
references.citation: Biochem J. 2009 Mar 1;418(2):233-46
references.pmid: 19196244
references.citation: Mol Microbiol. 2009 Mar;71(6):1341-52
references.pmid: 19208094
references.citation: EMBO J. 2010 Apr 21;29(8):1331-47
references.pmid: 20300065
references.citation: Nat Rev Mol Cell Biol. 2010 May;11(5):329-41
references.pmid: 20379207
references.citation: Mol Biol Cell. 2001 Jan;12(1):155-70
references.pmid: 11160830
references.citation: EMBO J. 2001 Feb 15;20(4):683-93
references.pmid: 11179213
references.citation: J Cell Biol. 2001 Jun 25;153(7):1369-80
references.pmid: 11425868
references.citation: Mol Biol Cell. 2012 Apr;23(8):1533-45
references.pmid: 22337770
references.citation: PLoS One. 2012;7(8):e43668
references.pmid: 22928013
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20485-90
references.pmid: 23197834
references.citation: Traffic. 2013 Feb;14(2):219-32
references.pmid: 23167963
references.citation: J Cell Biol. 2014 Apr 14;205(1):113-26
references.pmid: 24711504
references.citation: J Cell Biol. 2001 Aug 6;154(3):631-44
references.pmid: 11489920
references.citation: J Cell Biol. 2001 Oct 1;155(1):19-25
references.pmid: 11581283
references.citation: Curr Biol. 2001 Oct 16;11(20):1631-5
references.pmid: 11676926
references.citation: Mol Biol Cell. 2002 Apr;13(4):1190-202
references.pmid: 11950931
references.citation: Biochem J. 2002 Sep 15;366(Pt 3):689-704
references.pmid: 12061891
references.citation: Mol Biol Cell. 2002 Dec;13(12):4317-32
references.pmid: 12475955
references.citation: Mol Cell Biol. 2003 Apr;23(7):2501-14
references.pmid: 12640132
references.citation: Mol Cell Biol. 2003 Sep;23(18):6494-506
references.pmid: 12944476
references.citation: Traffic. 2003 Nov;4(11):754-71
references.pmid: 14617358
references.citation: PLoS Biol. 2012 Jan;10(1):e1001245
references.pmid: 22272187
references.citation: J Biol Chem. 2004 Aug 27;279(35):36982-92
references.pmid: 15210698
references.citation: Nat Chem Biol. 2010 Jul;6(7):507-13
references.pmid: 20559318
references.citation: J Pharm Biomed Anal. 2010 Nov 2;53(3):552-8
references.pmid: 20399587
references.citation: J Cell Biol. 2010 Nov 29;191(5):999-1012
references.pmid: 21115805
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20726-31
references.pmid: 21071675
references.citation: Mol Biol Cell. 2011 Jan 15;22(2):216-29
references.pmid: 21119004
references.citation: EMBO J. 2011 Aug 31;30(17):3481-500
references.pmid: 21878991
references.citation: Biochem J. 2000 Oct 1;351(Pt 1):19-31
references.pmid: 11001876
references.citation: J Cell Biol. 2000 Dec 25;151(7):1353-68
references.pmid: 11134066
references.citation: Tanpakushitsu Kakusan Koso. 2000 Oct;45(14):2405-14
references.pmid: 11051842
references.citation: EMBO J. 2000 Sep 1;19(17):4577-88
references.pmid: 10970851
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8910-5
references.pmid: 10900271
references.citation: Mol Biol Cell. 2000 Mar;11(3):807-17
references.pmid: 10712501
references.citation: Nat Cell Biol. 1999 Aug;1(4):249-52
references.pmid: 10559924
references.citation: J Cell Sci. 2006 Feb 1;119(Pt 3):571-81
references.pmid: 16443754
references.citation: J Cell Biol. 2004 Dec 20;167(6):1087-98
references.pmid: 15611334
references.citation: J Biol Chem. 1999 Jun 18;274(25):17794-805
references.pmid: 10364223
references.citation: J Cell Biol. 1998 Dec 14;143(6):1647-59
references.pmid: 9852157
references.citation: J Biol Chem. 1998 Nov 13;273(46):30379-90
references.pmid: 9804802
references.citation: EMBO Rep. 2004 Jun;5(6):590-5
references.pmid: 15133481
references.citation: Biochem J. 1991 Jan 1;273(Pt 1):63-6
references.pmid: 1846531
references.citation: J Cell Biol. 1994 Mar;124(5):677-88
references.pmid: 8120091