Phosphatidylinositol 3-Monophosphate Is Involved in Apicoplast Biogenesis
Apicomplexan parasites cause devastating diseases including malaria and toxoplasmosis. They harbour a plastid-like, non-photosynthetic organelle of algal origin, the apicoplast, which fulfils critical functions for parasite survival. Because of its essential and original metabolic pathways, the apicoplast has become a target for the development of new anti-apicomplexan drugs. Here we show that the lipid phosphatidylinositol 3-monophosphate (PI3P) is involved in apicoplast biogenesis in Toxoplasma gondii. In yeast and mammalian cells, PI3P is concentrated on early endosomes and regulates trafficking of endosomal compartments. Imaging of PI3P in T. gondii showed that the lipid was associated with the apicoplast and apicoplast protein-shuttling vesicles. Interference with regular PI3P function by over-expression of a PI3P specific binding module in the parasite led to the accumulation of vesicles containing apicoplast peripheral membrane proteins around the apicoplast and, ultimately, to the loss of the organelle. Accordingly, inhibition of the PI3P-synthesising kinase interfered with apicoplast biogenesis. These findings point to an unexpected implication for this ubiquitous lipid and open new perspectives on how nuclear encoded proteins traffic to the apicoplast. This study also highlights the possibility of developing specific pharmacological inhibitors of the parasite PI3-kinase as novel anti-apicomplexan drugs.
Vyšlo v časopise:
Phosphatidylinositol 3-Monophosphate Is Involved in Apicoplast Biogenesis. PLoS Pathog 7(2): e32767. doi:10.1371/journal.ppat.1001286
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1001286
Souhrn
Apicomplexan parasites cause devastating diseases including malaria and toxoplasmosis. They harbour a plastid-like, non-photosynthetic organelle of algal origin, the apicoplast, which fulfils critical functions for parasite survival. Because of its essential and original metabolic pathways, the apicoplast has become a target for the development of new anti-apicomplexan drugs. Here we show that the lipid phosphatidylinositol 3-monophosphate (PI3P) is involved in apicoplast biogenesis in Toxoplasma gondii. In yeast and mammalian cells, PI3P is concentrated on early endosomes and regulates trafficking of endosomal compartments. Imaging of PI3P in T. gondii showed that the lipid was associated with the apicoplast and apicoplast protein-shuttling vesicles. Interference with regular PI3P function by over-expression of a PI3P specific binding module in the parasite led to the accumulation of vesicles containing apicoplast peripheral membrane proteins around the apicoplast and, ultimately, to the loss of the organelle. Accordingly, inhibition of the PI3P-synthesising kinase interfered with apicoplast biogenesis. These findings point to an unexpected implication for this ubiquitous lipid and open new perspectives on how nuclear encoded proteins traffic to the apicoplast. This study also highlights the possibility of developing specific pharmacological inhibitors of the parasite PI3-kinase as novel anti-apicomplexan drugs.
Zdroje
1. VanhaesebroeckB
LeeversSJ
PanayotouG
WaterfieldMD
1997 Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22 267 272
2. FosterFM
TraerCJ
AbrahamSM
FryMJ
2003 The phosphoinositide (PI) 3-kinase family. J Cell Sci 116 3037 3040
3. VanhaesebroeckB
LeeversSJ
AhmadiK
TimmsJ
KatsoR
2001 Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70 535 602
4. HermanPK
EmrSD
1990 Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol Cell Biol 10 6742 6754
5. OdorizziG
BabstM
EmrSD
2000 Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem Sci 25 229 235
6. LindmoK
StenmarkH
2006 Regulation of membrane traffic by phosphoinositide 3-kinases. J Cell Sci 119 605 614
7. KraussM
HauckeV
2007 Phosphoinositide-metabolizing enzymes at the interface between membrane traffic and cell signalling. EMBO Rep 8 241 246
8. StenmarkH
AaslandR
DriscollPC
2002 The phosphatidylinositol 3-phosphate-binding FYVE finger. FEBS Lett 513 77 84
9. EllsonCD
AndrewsS
StephensLR
HawkinsPT
2002 The PX domain: a new phosphoinositide-binding module. J Cell Sci 115 1099 1105
10. KohlerS
DelwicheCF
DennyPW
TilneyLG
WebsterP
1997 A plastid of probable green algal origin in Apicomplexan parasites. Science 275 1485 1489
11. McFaddenGI
ReithME
MunhollandJ
Lang-UnnaschN
1996 Plastid in human parasites. Nature 381 482
12. RobibaroB
StedmanTT
CoppensI
NgoHM
PypaertM
2002 Toxoplasma gondii Rab5 enhances cholesterol acquisition from host cells. Cell Microbiol 4 139 152
13. ShawMK
RoosDS
TilneyLG
1998 Acidic compartments and rhoptry formation in Toxoplasma gondii. Parasitology 117 Pt 5 435 443
14. NgoHM
YangM
JoinerKA
2004 Are rhoptries in Apicomplexan parasites secretory granules or secretory lysosomal granules? Mol Microbiol 52 1531 1541
15. GajriaB
BahlA
BrestelliJ
DommerJ
FischerS
2008 ToxoDB: an integrated Toxoplasma gondii database resource. Nucleic Acids Res 36 D553 556
16. BackerJM
2008 The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem J 410 1 17
17. GilloolyDJ
MorrowIC
LindsayM
GouldR
BryantNJ
2000 Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. Embo J 19 4577 4588
18. HallBS
Gabernet-CastelloC
VoakA
GouldingD
NatesanSK
2006 TbVps34, the trypanosome orthologue of Vps34, is required for Golgi complex segregation. J Biol Chem 281 27600 27612
19. VermeerJE
van LeeuwenW
Tobena-SantamariaR
LaxaltAM
JonesDR
2006 Visualization of PtdIns3P dynamics in living plant cells. Plant J 47 687 700
20. SheffieldHG
MeltonML
1968 The fine structure and reproduction of Toxoplasma gondii. J Parasitol 54 209 226
21. NishiM
HuK
MurrayJM
RoosDS
2008 Organellar dynamics during the cell cycle of Toxoplasma gondii. J Cell Sci 121 1559 1568
22. Herm-GotzA
Agop-NersesianC
MunterS
GrimleyJS
WandlessTJ
2007 Rapid control of protein level in the apicomplexan Toxoplasma gondii. Nat Methods 4 1003 1005
23. BanaszynskiLA
SellmyerMA
ContagCH
WandlessTJ
ThorneSH
2008 Chemical control of protein stability and function in living mice. Nat Med 14 1123 1127
24. GaullierJM
SimonsenA
D'ArrigoA
BremnesB
StenmarkH
1998 FYVE fingers bind PtdIns(3)P. Nature 394 432 433
25. StriepenB
CrawfordMJ
ShawMK
TilneyLG
SeeberF
2000 The plastid of Toxoplasma gondii is divided by association with the centrosomes. J Cell Biol 151 1423 1434
26. PocciaD
LarijaniB
2009 Phosphatidylinositol metabolism and membrane fusion. Biochem J 418 233 246
27. van DoorenGG
ReiffSB
TomovaC
MeissnerM
HumbelBM
2009 A novel dynamin-related protein has been recruited for apicoplast fission in Toxoplasma gondii. Curr Biol 19 267 276
28. WalkerEH
PacoldME
PerisicO
StephensL
HawkinsPT
2000 Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6 909 919
29. FicheraME
BhopaleMK
RoosDS
1995 In vitro assays elucidate peculiar kinetics of clindamycin action against Toxoplasma gondii. Antimicrob Agents Chemother 39 1530 1537
30. PfefferkornER
NothnagelRF
BorotzSE
1992 Parasiticidal effect of clindamycin on Toxoplasma gondii grown in cultured cells and selection of a drug-resistant mutant. Antimicrob Agents Chemother 36 1091 1096
31. HeCY
ShawMK
PletcherCH
StriepenB
TilneyLG
2001 A plastid segregation defect in the protozoan parasite Toxoplasma gondii. Embo J 20 330 339
32. DeRocherAE
CoppensI
KarnatakiA
GilbertLA
RomeME
2008 A thioredoxin family protein of the apicoplast periphery identifies abundant candidate transport vesicles in Toxoplasma gondii. Eukaryot Cell 7 1518 1529
33. KarnatakiA
DerocherAE
CoppensI
FeaginJE
ParsonsM
2007 A membrane protease is targeted to the relict plastid of toxoplasma via an internal signal sequence. Traffic 8 1543 1553
34. KarnatakiA
DerocherA
CoppensI
NashC
FeaginJE
2007 Cell cycle-regulated vesicular trafficking of Toxoplasma APT1, a protein localized to multiple apicoplast membranes. Mol Microbiol 63 1653 1668
35. ParsonsM
KarnatakiA
DerocherAE
2009 Evolving insights into protein trafficking to the multiple compartments of the apicomplexan plastid. J Eukaryot Microbiol 56 214 220
36. NicholsBA
ChiappinoML
O'ConnorGR
1983 Secretion from the rhoptries of Toxoplasma gondii during host-cell invasion. J Ultrastruct Res 83 85 98
37. FiliN
CallejaV
WoscholskiR
ParkerPJ
LarijaniB
2006 Compartmental signal modulation: Endosomal phosphatidylinositol 3-phosphate controls endosome morphology and selective cargo sorting. Proc Natl Acad Sci U S A 103 15473 15478
38. VieiraOV
BucciC
HarrisonRE
TrimbleWS
LanzettiL
2003 Modulation of Rab5 and Rab7 recruitment to phagosomes by phosphatidylinositol 3-kinase. Mol Cell Biol 23 2501 2514
39. ElliottDA
McIntoshMT
HosgoodHD3rd
ChenS
ZhangG
2008 Four distinct pathways of hemoglobin uptake in the malaria parasite Plasmodium falciparum. Proc Natl Acad Sci U S A 105 2463 2468
40. VaidA
RanjanR
SmytheWA
HoppeHC
SharmaP
2010 PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking. Blood 115 2500 2507
41. TawkL
ChicanneG
DubremetzJF
RichardV
PayrastreB
2010 Phosphatidylinositol 3-Phosphate, an Essential Lipid in Plasmodium, Localizes to the Food Vacuole Membrane and the Apicoplast. Eukaryot Cell 9 1519 1530
42. DonaldRG
CarterD
UllmanB
RoosDS
1996 Insertional tagging, cloning, and expression of the Toxoplasma gondii hypoxanthine-xanthine-guanine phosphoribosyltransferase gene. Use as a selectable marker for stable transformation. J Biol Chem 271 14010 14019
43. BesteiroS
Bertrand-MichelJ
LebrunM
VialH
DubremetzJF
2008 Lipidomic analysis of Toxoplasma gondii tachyzoites rhoptries: further insights into the role of cholesterol. Biochem J 415 87 96
44. PayrastreB
2004 Phosphoinositides: lipid kinases and phosphatases. Methods Mol Biol 273 201 212
45. ReissM
ViebigN
BrechtS
FourmauxMN
SoeteM
2001 Identification and characterization of an escorter for two secretory adhesins in Toxoplasma gondii. J Cell Biol 152 563 578
46. CeredeO
DubremetzJF
SoeteM
DesleeD
VialH
2005 Synergistic role of micronemal proteins in Toxoplasma gondii virulence. J Exp Med 201 453 463
47. AgrawalS
Van DoorenGG
BeattyWL
StriepenB
2009 Genetic evidence that endosymbiont-derived ERAD system functions in import of apicoplast proteins. J Biol Chem 27 33683 33691
48. CouvreurG
SadakA
FortierB
DubremetzJF
1988 Surface antigens of Toxoplasma gondii. Parasitol 97 1 10
49. SadakA
TaghyZ
FortierB
DubremetzJF
1988 Characterization of a family of rhoptry proteins of Toxoplasma gondii. Mol Biochem Parasitol 29 203 211
50. AchbarouA
Mercereau-PuijalonO
AuthemanJM
FortierB
CamusD
1991 Characterization of microneme proteins of Toxoplasma gondii. Mol Biochem Parasitol 47 223 233
51. BolteS
CordelieresFP
2006 A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224 213 232
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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