The Machinery at Endoplasmic Reticulum-Plasma Membrane Contact Sites Contributes to Spatial Regulation of Multiple Effector Proteins
The intracellular pathogen Legionella pneumophila encodes at least 270 effectors that modulate trafficking of the pathogen-occupied vacuole. The mechanisms by which effectors are controlled in host cells are of key interest. Spatial and temporal regulation of effector function has been proposed to involve effector binding to host phosphoinositides. We present results showing that L. pneumophila utilizes the host kinase PI4KIIIα to generate PI4P on the bacterial vacuole and this signature mediates the localization of DrrA and subsequent recruitment of the GTPase Rab1. Additionally, it was found that the host PI4P phosphatase Sac1 was involved in consuming PI4P on the vacuole, which reduced DrrA-mediated recruitment of Rab1 to the LCV. Our data supports the recent concept that PI4KIIIα is important for generation of the plasma-membrane pool of PI4P in host cells, and demonstrates a functional consequence for PI4P-binding by an L. pneumophila effector protein.
Vyšlo v časopise:
The Machinery at Endoplasmic Reticulum-Plasma Membrane Contact Sites Contributes to Spatial Regulation of Multiple Effector Proteins. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004222
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004222
Souhrn
The intracellular pathogen Legionella pneumophila encodes at least 270 effectors that modulate trafficking of the pathogen-occupied vacuole. The mechanisms by which effectors are controlled in host cells are of key interest. Spatial and temporal regulation of effector function has been proposed to involve effector binding to host phosphoinositides. We present results showing that L. pneumophila utilizes the host kinase PI4KIIIα to generate PI4P on the bacterial vacuole and this signature mediates the localization of DrrA and subsequent recruitment of the GTPase Rab1. Additionally, it was found that the host PI4P phosphatase Sac1 was involved in consuming PI4P on the vacuole, which reduced DrrA-mediated recruitment of Rab1 to the LCV. Our data supports the recent concept that PI4KIIIα is important for generation of the plasma-membrane pool of PI4P in host cells, and demonstrates a functional consequence for PI4P-binding by an L. pneumophila effector protein.
Zdroje
1. TilneyLG, HarbOS, ConnellyPS, RobinsonCG, RoyCR (2001) How the parasitic bacterium Legionella pneumophila modifies its phagosome and transforms it into rough ER: implications for conversion of plasma membrane to the ER membrane. J Cell Sci 114: 4637–4650.
2. DerreI, IsbergRR (2004) Legionella pneumophila replication vacuole formation involves rapid recruitment of proteins of the early secretory system. Infect Immun 72: 3048–3053.
3. KaganJC, RoyCR (2002) Legionella phagosomes intercept vesicular traffic from endoplasmic reticulum exit sites. Nat Cell Biol 4: 945–954.
4. KaganJC, SteinMP, PypaertM, RoyCR (2004) Legionella subvert the functions of Rab1 and Sec22b to create a replicative organelle. J Exp Med 199: 1201–1211.
5. ArasakiK, RoyCR (2010) Legionella pneumophila promotes functional interactions between plasma membrane syntaxins and Sec22b. Traffic 11: 587–600.
6. PetkovicM, JemaielA, DasteF, SpechtCG, IzeddinI, et al. (2014) The SNARE Sec22b has a non-fusogenic function in plasma membrane expansion. Nat Cell Biol 16 (5) 434–44.
7. MachnerMP, IsbergRR (2006) Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev Cell 11: 47–56.
8. MurataT, DelpratoA, IngmundsonA, ToomreDK, LambrightDG, et al. (2006) The Legionella pneumophila effector protein DrrA is a Rab1 guanine nucleotide-exchange factor. Nat Cell Biol 8: 971–977.
9. StenmarkH (2009) Rab GTPases as coordinators of vesicle traffic. Nat Rev Mol Cell Biol 10: 513–525.
10. IngmundsonA, DelpratoA, LambrightDG, RoyCR (2007) Legionella pneumophila proteins that regulate Rab1 membrane cycling. Nature 450: 365–369.
11. MachnerMP, IsbergRR (2007) A bifunctional bacterial protein links GDI displacement to Rab1 activation. Science 318: 974–977.
12. SchoebelS, OesterlinLK, BlankenfeldtW, GoodyRS, ItzenA (2009) RabGDI displacement by DrrA from Legionella is a consequence of its guanine nucleotide exchange activity. Mol Cell 36: 1060–1072.
13. ArasakiK, ToomreDK, RoyCR (2012) The Legionella pneumophila Effector DrrA Is Sufficient to Stimulate SNARE-Dependent Membrane Fusion. Cell Host Microbe 11: 46–57.
14. NeunuebelMR, ChenY, GasparAH, BacklundPSJr, YergeyA, et al. (2011) De-AMPylation of the Small GTPase Rab1 by the Pathogen Legionella pneumophila. Science 333 (6041) 453–6.
15. RobinsonCG, RoyCR (2006) Attachment and fusion of endoplasmic reticulum with vacuoles containing Legionella pneumophila. Cell Microbiol 8: 793–805.
16. MukherjeeS, LiuX, ArasakiK, McDonoughJ, GalanJE, et al. (2011) Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477: 103–106.
17. MullerMP, PetersH, BlumerJ, BlankenfeldtW, GoodyRS, et al. (2010) The Legionella effector protein DrrA AMPylates the membrane traffic regulator Rab1b. Science 329: 946–949.
18. GoodyPR, HellerK, OesterlinLK, MullerMP, ItzenA, et al. (2012) Reversible phosphocholination of Rab proteins by Legionella pneumophila effector proteins. Embo J 31: 1774–1784.
19. OesterlinLK, GoodyRS, ItzenA (2012) Posttranslational modifications of Rab proteins cause effective displacement of GDP dissociation inhibitor. Proc Natl Acad Sci U S A 109: 5621–5626.
20. RigdenDJ (2011) Identification and modelling of a PPM protein phosphatase fold in the Legionella pneumophila deAMPylase SidD. FEBS Lett 585: 2749–2754.
21. TanY, LuoZQ (2011) Legionella pneumophila SidD is a deAMPylase that modifies Rab1. Nature 475: 506–509.
22. TanY, ArnoldRJ, LuoZQ (2011) Legionella pneumophila regulates the small GTPase Rab1 activity by reversible phosphorylcholination. Proc Natl Acad Sci U S A 108: 21212–21217.
23. BrombacherE, UrwylerS, RagazC, WeberSS, KamiK, et al. (2009) Rab1 guanine nucleotide exchange factor SidM is a major phosphatidylinositol 4-phosphate-binding effector protein of Legionella pneumophila. J Biol Chem 284: 4846–4856.
24. SchoebelS, BlankenfeldtW, GoodyRS, ItzenA (2010) High-affinity binding of phosphatidylinositol 4-phosphate by Legionella pneumophila DrrA. EMBO Rep 11: 598–604.
25. ZhuY, HuL, ZhouY, YaoQ, LiuL, et al. (2010) Structural mechanism of host Rab1 activation by the bifunctional Legionella type IV effector SidM/DrrA. Proc Natl Acad Sci U S A 107: 4699–4704.
26. HammondGR, MachnerMP, BallaT (2014) A novel probe for phosphatidylinositol 4-phosphate reveals multiple pools beyond the Golgi. J Cell Biol 205: 113–126.
27. Di PaoloG, De CamilliP (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443: 651–657.
28. NiggliV (2005) Regulation of protein activities by phosphoinositide phosphates. Annu Rev Cell Dev Biol 21: 57–79.
29. VicinanzaM, D'AngeloG, Di CampliA, De MatteisMA (2008) Function and dysfunction of the PI system in membrane trafficking. Embo J 27: 2457–2470.
30. VicinanzaM, D'AngeloG, Di CampliA, De MatteisMA (2008) Phosphoinositides as regulators of membrane trafficking in health and disease. Cell Mol Life Sci 65: 2833–2841.
31. DiNittoJP, CroninTC, LambrightDG (2003) Membrane recognition and targeting by lipid-binding domains. Sci STKE 2003: re16.
32. Pizarro-CerdaJ, CossartP (2004) Subversion of phosphoinositide metabolism by intracellular bacterial pathogens. Nat Cell Biol 6: 1026–1033.
33. WeberSS, RagazC, HilbiH (2009) Pathogen trafficking pathways and host phosphoinositide metabolism. Mol Microbiol 71: 1341–1352.
34. WeberSS, RagazC, ReusK, NyfelerY, HilbiH (2006) Legionella pneumophila exploits PI(4)P to anchor secreted effector proteins to the replicative vacuole. PLoS Pathog 2: e46.
35. RagazC, PietschH, UrwylerS, TiadenA, WeberSS, et al. (2008) The Legionella pneumophila phosphatidylinositol-4 phosphate-binding type IV substrate SidC recruits endoplasmic reticulum vesicles to a replication-permissive vacuole. Cellular Microbiology 10: 2416–2433.
36. HsuF, ZhuW, BrennanL, TaoL, LuoZQ, et al. (2012) Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase. Proc Natl Acad Sci U S A 109: 13567–13572.
37. D'AngeloG, VicinanzaM, Di CampliA, De MatteisMA (2008) The multiple roles of PtdIns(4)P – not just the precursor of PtdIns(4,5)P2. J Cell Sci 121: 1955–1963.
38. BallaA, BallaT (2006) Phosphatidylinositol 4-kinases: old enzymes with emerging functions. Trends Cell Biol 16: 351–361.
39. DowningGJ, KimS, NakanishiS, CattKJ, BallaT (1996) Characterization of a soluble adrenal phosphatidylinositol 4-kinase reveals wortmannin sensitivity of type III phosphatidylinositol kinases. Biochemistry 35: 3587–3594.
40. BallaA, TuymetovaG, TsiomenkoA, VarnaiP, BallaT (2005) 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. Mol Biol Cell 16: 1282–1295.
41. DowlerS, CurrieRA, CampbellDG, DeakM, KularG, et al. (2000) Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochem J 351: 19–31.
42. LevineTP, MunroS (2002) Targeting of Golgi-specific pleckstrin homology domains involves both PtdIns 4-kinase-dependent and -independent components. Curr Biol 12: 695–704.
43. YuJW, MendrolaJM, AudhyaA, SinghS, KeletiD, et al. (2004) Genome-wide analysis of membrane targeting by S. cerevisiae pleckstrin homology domains. Mol Cell 13: 677–688.
44. Walch-SolimenaC, NovickP (1999) The yeast phosphatidylinositol-4-OH kinase pik1 regulates secretion at the Golgi. Nat Cell Biol 1: 523–525.
45. WeixelKM, Blumental-PerryA, WatkinsSC, AridorM, WeiszOA (2005) Distinct Golgi populations of phosphatidylinositol 4-phosphate regulated by phosphatidylinositol 4-kinases. J Biol Chem 280: 10501–10508.
46. WongK, Meyers ddR, CantleyLC (1997) Subcellular locations of phosphatidylinositol 4-kinase isoforms. J Biol Chem 272: 13236–13241.
47. HammondGR, FischerMJ, AndersonKE, HoldichJ, KoteciA, et al. (2012) PI4P and PI(4,5)P2 are essential but independent lipid determinants of membrane identity. Science 337: 727–730.
48. NakatsuF, BaskinJM, ChungJ, TannerLB, ShuiG, et al. (2012) PtdIns4P synthesis by PI4KIIIα at the plasma membrane and its impact on plasma membrane identity. The Journal of Cell Biology 199: 1003–1016.
49. BairdD, StefanC, AudhyaA, WeysS, EmrSD (2008) Assembly of the PtdIns 4-kinase Stt4 complex at the plasma membrane requires Ypp1 and Efr3. J Cell Biol 183: 1061–1074.
50. LevineT, LoewenC (2006) Inter-organelle membrane contact sites: through a glass, darkly. Curr Opin Cell Biol 18: 371–378.
51. StefanCJ, ManfordAG, BairdD, Yamada-HanffJ, MaoY, et al. (2011) Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites. Cell 144: 389–401.
52. Del CampoCM, MishraAK, WangYH, RoyCR, JanmeyPA, et al. (2014) Structural Basis for PI(4)P-Specific Membrane Recruitment of the Legionella pneumophila Effector DrrA/SidM. Structure 22 (3) 397–408.
53. GodiA, Di CampliA, KonstantakopoulosA, Di TullioG, AlessiDR, et al. (2004) FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P. Nat Cell Biol 6: 393–404.
54. VarnaiP, BallaT (1998) Visualization of phosphoinositides that bind pleckstrin homology domains: calcium- and agonist-induced dynamic changes and relationship to myo-[3H]inositol-labeled phosphoinositide pools. J Cell Biol 143: 501–510.
55. ManfordA, XiaT, SaxenaAK, StefanC, HuF, et al. (2010) Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function. Embo J 29: 1489–1498.
56. BlumerJ, ReyJ, DehmeltL, MazelT, WuYW, et al. (2013) RabGEFs are a major determinant for specific Rab membrane targeting. J Cell Biol 200: 287–300.
57. LiuY, KahnRA, PrestegardJH (2014) Interaction of Fapp1 with Arf1 and PI4P at a membrane surface: an example of coincidence detection. Structure 22: 421–430.
58. HancockJF, CadwalladerK, PatersonH, MarshallCJ (1991) A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of ras proteins. Embo J 10: 4033–4039.
59. WeberSS, RagazC, HilbiH (2009) The inositol polyphosphate 5-phosphatase OCRL1 restricts intracellular growth of Legionella, localizes to the replicative vacuole and binds to the bacterial effector LpnE. Cell Microbiol 11: 442–460.
60. ChoudhuryR, DiaoA, ZhangF, EisenbergE, Saint-PolA, et al. (2005) Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network. Mol Biol Cell 16: 3467–3479.
61. SwanLE, TomasiniL, PirruccelloM, LunardiJ, De CamilliP (2010) Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1. Proc Natl Acad Sci U S A 107: 3511–3516.
62. ErdmannKS, MaoY, McCreaHJ, ZoncuR, LeeS, et al. (2007) A role of the Lowe syndrome protein OCRL in early steps of the endocytic pathway. Dev Cell 13: 377–390.
63. UngewickellA, WardME, UngewickellE, MajerusPW (2004) The inositol polyphosphate 5-phosphatase Ocrl associates with endosomes that are partially coated with clathrin. Proc Natl Acad Sci U S A 101: 13501–13506.
64. ChoudhuryR, NoakesCJ, McKenzieE, KoxC, LoweM (2009) Differential clathrin binding and subcellular localization of OCRL1 splice isoforms. J Biol Chem 284: 9965–9973.
65. HouX, HagemannN, SchoebelS, BlankenfeldtW, GoodyRS, et al. (2011) A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1. Embo J 30: 1659–1670.
66. BallaA, KimYJ, VarnaiP, SzentpeteryZ, KnightZ, et al. (2008) Maintenance of hormone-sensitive phosphoinositide pools in the plasma membrane requires phosphatidylinositol 4-kinase IIIalpha. Mol Biol Cell 19: 711–721.
67. RoyA, LevineTP (2004) Multiple pools of phosphatidylinositol 4-phosphate detected using the pleckstrin homology domain of Osh2p. J Biol Chem 279: 44683–44689.
68. GiordanoF, SahekiY, Idevall-HagrenO, ColomboSF, PirruccelloM, et al. (2013) PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153: 1494–1509.
69. HeidtmanM, ChenEJ, MoyMY, IsbergRR (2009) Large-scale identification of Legionella pneumophila Dot/Icm substrates that modulate host cell vesicle trafficking pathways. Cell Microbiol 11: 230–248.
70. RoyCR, IsbergRR (1997) Topology of Legionella pneumophila DotA: an inner membrane protein required for replication in macrophages. Infect Immun 65: 571–578.
71. MerriamJJ, MathurR, Maxfield-BoumilR, IsbergRR (1997) Analysis of the Legionella pneumophila fliI gene: intracellular growth of a defined mutant defective for flagellum biosynthesis. Infect Immun 65: 2497–2501.
72. CoersJ, VanceRE, FontanaMF, DietrichWF (2007) Restriction of Legionella pneumophila growth in macrophages requires the concerted action of cytokine and Naip5/Ipaf signalling pathways. Cell Microbiol 9: 2344–2357.
73. KaganJC, MurataT, RoyCR (2005) Analysis of Rab1 recruitment to vacuoles containing Legionella pneumophila. Meth Enzymol 403: 71–81.
74. MarimFM, SilveiraTN, LimaDSJr, ZamboniDS (2010) A method for generation of bone marrow-derived macrophages from cryopreserved mouse bone marrow cells. PLoS One 5: e15263.
75. ZamboniDS, KobayashiKS, KohlsdorfT, OguraY, LongEM, et al. (2006) The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nature Immunology 7: 318–325.
76. RenT, ZamboniDS, RoyCR, DietrichWF, VanceRE (2006) Flagellin-deficient Legionella mutants evade caspase-1- and Naip5-mediated macrophage immunity. PLoS Pathog 2: e18.
77. NakatsuF, PereraRM, LucastL, ZoncuR, DominJ, et al. (2010) The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics. J Cell Biol 190: 307–315.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2014 Číslo 7
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Molecular and Cellular Mechanisms of KSHV Oncogenesis of Kaposi's Sarcoma Associated with HIV/AIDS
- Holobiont–Holobiont Interactions: Redefining Host–Parasite Interactions
- Helminth Infections, Type-2 Immune Response, and Metabolic Syndrome
- BCKDH: The Missing Link in Apicomplexan Mitochondrial Metabolism Is Required for Full Virulence of and