Juxtamembrane Shedding of AMA1 Is Sequence Independent and Essential, and Helps Evade Invasion-Inhibitory Antibodies

English version České info

The malarial life cycle involves repeated rounds of intraerythrocytic replication interspersed by host cell rupture which releases merozoites that rapidly invade fresh erythrocytes. Apical membrane antigen-1 (AMA1) is a merozoite protein that plays a critical role in invasion. Antibodies against AMA1 prevent invasion and can protect against malaria in vivo, so AMA1 is of interest as a malaria vaccine candidate. AMA1 is efficiently shed from the invading parasite surface, predominantly through juxtamembrane cleavage by a membrane-bound protease called SUB2, but also by limited intramembrane cleavage. We have investigated the structural requirements for shedding of Plasmodium falciparum AMA1 (PfAMA1), and the consequences of its inhibition. Mutagenesis of the intramembrane cleavage site by targeted homologous recombination abolished intramembrane cleavage with no effect on parasite viability in vitro. Examination of PfSUB2-mediated shedding of episomally-expressed PfAMA1 revealed that the position of cleavage is determined primarily by its distance from the parasite membrane. Certain mutations at the PfSUB2 cleavage site block shedding, and parasites expressing these non-cleavable forms of PfAMA1 on a background of expression of the wild type gene invade and replicate normally in vitro. The non-cleavable PfAMA1 is also functional in invasion. However –⁠ in contrast to the intramembrane cleavage site -⁠ mutations that block PfSUB2-mediated shedding could not be stably introduced into the genomic pfama1 locus, indicating that some shedding of PfAMA1 by PfSUB2 is essential. Remarkably, parasites expressing shedding-resistant forms of PfAMA1 exhibit enhanced sensitivity to antibody-mediated inhibition of invasion. Drugs that inhibit PfSUB2 activity should block parasite replication and may also enhance the efficacy of vaccines based on AMA1 and other merozoite surface proteins.

Vyšlo v časopise: Juxtamembrane Shedding of AMA1 Is Sequence Independent and Essential, and Helps Evade Invasion-Inhibitory Antibodies. PLoS Pathog 7(12): e32767. doi:10.1371/journal.ppat.1002448
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002448

Souhrn

Zdroje

1. FraitureMBaxterRHSteinertSChelliahYFroletC 2009 Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium. Cell Host Microbe 5 273 284

2. BeesonJGOsierFHEngwerdaCR 2008 Recent insights into humoral and cellular immune responses against malaria. Trends Parasitol 24 578 584

3. O'DonnellRABlackmanMJ 2005 The role of malaria merozoite proteases in red blood cell invasion. Curr Opin Microbiol. 8 422 427

4. Soldati-FavreD 2008 Molecular dissection of host cell invasion by the apicomplexans: the glideosome. Parasite 15 197 205

5. DvorakJAMillerLHWhitehouseWCShiroishiT 1975 Invasion of erythrocytes by malaria merozoites. Science 187 748 750

6. AikawaMMillerLHJohnsonJRabbegeJ 1978 Erythrocyte entry by malarial parasites. A moving junction between erythrocyte and parasite. J Cell Biol 77 72 82

7. GilsonPRCrabbBS 2009 Morphology and kinetics of the three distinct phases of red blood cell invasion by Plasmodium falciparum merozoites. Int J Parasitol 39 91 96

8. HowellSAHackettFJongcoAMWithers-MartinezCKimK 2005 Distinct mechanisms govern proteolytic shedding of a key invasion protein in apicomplexan pathogens. Mol Microbiol 57 1342 1356

9. BlackmanMJHeidrichHGDonachieSMcBrideJSHolderAA 1990 A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies. J Exp Med 172 379 382

10. BlackmanMJChappelJAShaiSHolderAA 1993 A conserved parasite serine protease processes the Plasmodium falciparum merozoite surface protein-1. Mol Biochem Parasitol 62 103 114

11. HarrisPKYeohSDluzewskiARO'DonnellRAWithers-MartinezC 2005 Molecular identification of a malaria merozoite surface sheddase. PLoS Pathog 1 241 251

12. HowellSAWellIFleckSLKettleboroughCCollinsCR 2003 A single malaria merozoite serine protease mediates shedding of multiple surface proteins by juxtamembrane cleavage. J Biol Chem 278 23890 23898

13. GreenJLHindsLGraingerMKnuepferEHolderAA 2006 Plasmodium thrombospondin related apical merozoite protein (PTRAMP) is shed from the surface of merozoites by PfSUB2 upon invasion of erythrocytes. Mol Biochem Parasitol 150 114 117

14. BlackmanMJLingITNichollsSCHolderAA 1991 Proteolytic processing of the Plasmodium falciparum merozoite surface protein-1 produces a membrane-bound fragment containing two epidermal growth factor-like domains. Mol Biochem Parasitol 49 29 33

15. SchlondorffJBlobelCP 1999 Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding. J Cell Sci 112 ( Pt 21) 3603 3617

16. WangXHeKGerhartMHuangYJiangJ 2002 Metalloprotease-mediated GH receptor proteolysis and GHBP shedding. Determination of extracellular domain stem region cleavage site. J Biol Chem 277 50510 50519

17. SchwagerSLChubbAJWoodmanZLYanLMenteleR 2001 Cleavage of disulfide-bridged stalk domains during shedding of angiotensin-converting enzyme occurs at multiple juxtamembrane sites. Biochemistry 40 15624 15630

18. PangSChubbAJSchwagerSLEhlersMRSturrockED 2001 Roles of the juxtamembrane and extracellular domains of angiotensin-converting enzyme in ectodomain shedding. Biochem J 358 185 192

19. TanakaKChazenbalkGDMcLachlanSMRapoportB 2000 Evidence that cleavage of the thyrotropin receptor involves a "molecular ruler" mechanism: deletion of amino acid residues 305-320 causes a spatial shift in cleavage site 1 independent of amino acid motif. Endocrinology 141 3573 3577

20. MaruyamaKKametaniFUsamiMYamao-HarigayaWTanakaK 1991 "Secretase," Alzheimer amyloid protein precursor secreting enzyme is not sequence-specific. Biochem Biophys Res Commun 179 1670 1676

21. O'DonnellRAHackettFHowellSATreeckMStruckN 2006 Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite. J Cell Biol 174 1023 1033

22. BakerRPWijetilakaRUrbanS 2006 Two Plasmodium rhomboid proteases preferentially cleave different adhesins implicated in all invasive stages of malaria. PLoS Pathog 2 e113

23. BuguliskisJSBrossierFShumanJSibleyLD 2010 Rhomboid 4 (ROM4) affects the processing of surface adhesins and facilitates host cell invasion by Toxoplasma gondii. PLoS Pathog 6 e1000858

24. SantosJMFergusonDJBlackmanMJSoldati-FavreD 2011 Intramembrane Cleavage of AMA1 Triggers Toxoplasma to Switch from an Invasive to a Replicative Mode. Science 331 473 477

25. UzureauPBaraleJCJanseCJWatersAPBretonCB 2004 Gene targeting demonstrates that the Plasmodium berghei subtilisin PbSUB2 is essential for red cell invasion and reveals spontaneous genetic recombination events. Cell Microbiol 6 65 78

26. FleckSLBirdsallBBabonJDluzewskiARMartinSR 2003 Suramin and suramin analogues inhibit merozoite surface protein-1 secondary processing and erythrocyte invasion by the malaria parasite Plasmodium falciparum. J Biol Chem 278 47670 47677

27. BlackmanMJScott-FinniganTJShaiSHolderAA 1994 Antibodies inhibit the protease-mediated processing of a malaria merozoite surface protein. J Exp Med 180 389 393

28. UthaipibullCAufieroBSyedSEHansenBGuevara PatinoJA 2001 Inhibitory and blocking monoclonal antibody epitopes on merozoite surface protein 1 of the malaria parasite Plasmodium falciparum. J Mol Biol 307 1381 1394

29. WoehlbierUEppCHackettFBlackmanMJBujardH 2010 Antibodies against multiple merozoite surface antigens of the human malaria parasite Plasmodium falciparum inhibit parasite maturation and red blood cell invasion. Malar J 9 77

30. DuttaSHaynesJDMochJKBarbosaALanarDE 2003 Invasion-inhibitory antibodies inhibit proteolytic processing of apical membrane antigen 1 of Plasmodium falciparum merozoites. Proc Natl Acad Sci U S A 100 12295 12300

31. DuttaSHaynesJDBarbosaAWareLASnavelyJD 2005 Mode of action of invasion-inhibitory antibodies directed against apical membrane antigen 1 of Plasmodium falciparum. Infect Immun 73 2116 2122

32. CollinsCRWithers-MartinezCHackettFBlackmanMJ 2009 An inhibitory antibody blocks interactions between components of the malarial invasion machinery. PLoS Pathog 5 e1000273

33. AlexanderDLArastu-KapurSDubremetzJFBoothroydJC 2006 Plasmodium falciparum AMA1 binds a rhoptry neck protein homologous to TgRON4, a component of the moving junction in Toxoplasma gondii. Eukaryot Cell 5 1169 1173

34. LamarqueMBesteiroSPapoinJRoquesMVulliez-Le NormandB 2011 The RON2-AMA1 interaction is a critical step in moving junction-dependent invasion by apicomplexan parasites. PLoS Pathog 7 e1001276

35. TonkinMLRoquesMLamarqueMHPugniereMDouguetD 2011 Host cell invasion by apicomplexan parasites: insights from the co-structure of AMA1 with a RON2 peptide. Science 333 463 467

36. TylerJSBoothroydJC 2011 The C-terminus of Toxoplasma RON2 provides the crucial link between AMA1 and the host-associated invasion complex. PLoS Pathog 7 e1001282

37. TrigliaTHealerJCaruanaSRHodderANAndersRF 2000 Apical membrane antigen 1 plays a central role in erythrocyte invasion by Plasmodium species. Mol Microbiol 38 706 718

38. O'DonnellRASaulACowmanAFCrabbBS 2000 Functional conservation of the malaria vaccine antigen MSP-119across distantly related Plasmodium species. Nat Med 6 91 95

39. DrewDRO'DonnellRASmithBJCrabbBS 2004 A common cross-species function for the double epidermal growth factor-like modules of the highly divergent plasmodium surface proteins MSP-1 and MSP-8. J Biol Chem 279 20147 20153

40. CombeAGiovanniniDCarvalhoTGSpathSBoissonB 2009 Clonal conditional mutagenesis in malaria parasites. Cell Host Microbe 5 386 396

41. MitalJMeissnerMSoldatiDWardGE 2005 Conditional Expression of Toxoplasma gondii Apical Membrane Antigen-1 (TgAMA1) Demonstrates That TgAMA1 Plays a Critical Role in Host Cell Invasion. Mol Biol Cell 16 4341 4349

42. HehlABLekutisCGriggMEBradleyPJDubremetzJF 2000 Toxoplasma gondii homologue of plasmodium apical membrane antigen 1 is involved in invasion of host cells. Infect Immun 68 7078 7086

43. GaffarFRYatsudaAPFranssenFFde VriesE 2004 Erythrocyte invasion by Babesia bovis merozoites is inhibited by polyclonal antisera directed against peptides derived from a homologue of Plasmodium falciparum apical membrane antigen 1. Infect Immun 72 2947 2955

44. LeykaufKTreeckMGilsonPRNeblTBraulkeT 2010 Protein kinase a dependent phosphorylation of apical membrane antigen 1 plays an important role in erythrocyte invasion by the malaria parasite. PLoS Pathog 6 e1000941

45. TreeckMZacherlSHerrmannSCabreraAKonoM 2009 Functional analysis of the leading malaria vaccine candidate AMA-1 reveals an essential role for the cytoplasmic domain in the invasion process. PLoS Pathog 5 e1000322

46. RemarqueEJFaberBWKockenCHThomasAW 2008 Apical membrane antigen 1: a malaria vaccine candidate in review. Trends Parasitol 24 74 84

47. HolderAA 2009 The carboxy-terminus of merozoite surface protein 1: structure, specific antibodies and immunity to malaria. Parasitology 136 1445 1456

48. MiuraKZhouHDioufAMoretzSEFayMP 2009 Anti-apical-membrane-antigen-1 antibody is more effective than anti-42-kilodalton-merozoite-surface-protein-1 antibody in inhibiting plasmodium falciparum growth, as determined by the in vitro growth inhibition assay. Clin Vaccine Immunol 16 963 968

49. MalkinEMDiemertDJMcArthurJHPerreaultJRMilesAP 2005 Phase 1 clinical trial of apical membrane antigen 1: an asexual blood-stage vaccine for Plasmodium falciparum malaria. Infect Immun 73 3677 3685

50. RoestenbergMRemarqueEde JongeEHermsenRBlythmanH 2008 Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02. PLoS One 3 e3960

51. SagaraIDickoAEllisRDFayMPDiawaraSI 2009 A randomized controlled phase 2 trial of the blood stage AMA1-C1/Alhydrogel malaria vaccine in children in Mali. Vaccine 27 3090 3098

52. SpringMDCummingsJFOckenhouseCFDuttaSReidlerR 2009 Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-1) administered in adjuvant system AS01B or AS02A. PLoS One 4 e5254

53. ThompsonFMPorterDWOkitsuSLWesterfeldNVogelD 2008 Evidence of blood stage efficacy with a virosomal malaria vaccine in a phase IIa clinical trial. PLoS One 3 e1493

54. OgutuBRApolloOJMcKinneyDOkothWSianglaJ 2009 Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya. PLoS One 4 e4708

55. CarruthersVBBlackmanMJ 2005 A new release on life: emerging concepts in proteolysis and parasite invasion. Mol Microbiol 55 1617 1630

56. BrossierFJewettTJLovettJLSibleyLD 2003 C-terminal processing of the toxoplasma protein MIC2 is essential for invasion into host cells. J Biol Chem 278 6229 6234

57. SaulA 1987 Kinetic constraints on the development of a malaria vaccine. Parasite Immunol 9 1 9

58. ZhouXWBlackmanMJHowellSACarruthersVB 2004 Proteomic analysis of cleavage events reveals a dynamic two-step mechanism for proteolysis of a key parasite adhesive complex. Mol Cell Proteomics. 3 565 576

59. OpitzCDi CristinaMReissMRuppertTCrisantiA 2002 Intramembrane cleavage of microneme proteins at the surface of the apicomplexan parasite Toxoplasma gondii. EMBO J 21 1577 1585

60. SchechterIBergerA 1967 On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 27 157 162

61. StrisovskyKSharpeHJFreemanM 2009 Sequence-specific intramembrane proteolysis: identification of a recognition motif in rhomboid substrates. Mol Cell 36 1048 1059

62. AkiyamaYMaegawaS 2007 Sequence features of substrates required for cleavage by GlpG, an Escherichia coli rhomboid protease. Mol Microbiol 64 1028 1037

63. CollinsCRWithers-MartinezCBentleyGABatchelorAHThomasAW 2007 Fine Mapping of an Epitope Recognized by an Invasion-inhibitory Monoclonal Antibody on the Malaria Vaccine Candidate Apical Membrane Antigen 1. J Biol Chem 282 7431 7441

64. PizarroJCNormandBVChesne-SeckMLCollinsCRWithers-MartinezC 2005 Crystal structure of the malaria vaccine candidate apical membrane antigen 1. Science 308 408 411

65. NarumDLThomasAW 1994 Differential localization of full-length and processed forms of PF83/AMA-1 an apical membrane antigen of Plasmodium falciparum merozoites. Mol Biochem Parasitol 67 59 68

66. HowellSAWithers-MartinezCKockenCHThomasAWBlackmanMJ 2001 Proteolytic processing and primary structure of Plasmodium falciparum apical membrane antigen-1. J Biol Chem 276 31311 31320

67. O'DonnellRAFreitas-JuniorLHPreiserPRWilliamsonDHDuraisinghM 2002 A genetic screen for improved plasmid segregation reveals a role for Rep20 in the interaction of Plasmodium falciparum chromosomes. EMBO J 21 1231 1239

68. VanhoofGGoossensFDe MeesterIHendriksDScharpeS 1995 Proline motifs in peptides and their biological processing. Faseb J 9 736 744

69. Chesne-SeckMLPizarroJCNormandBVCollinsCRBlackmanMJ 2005 Structural comparison of apical membrane antigen 1 orthologues and paralogues in apicomplexan parasites. Mol Biochem Parasitol 144 55 67

70. HarrisKSCaseyJLColeyAMMasciantonioRSaboJK 2005 Binding hot spot for invasion inhibitory molecules on Plasmodium falciparum apical membrane antigen 1. Infect Immun 73 6981 6989

71. HarrisKSCaseyJLColeyAMKarasJASaboJK 2009 Rapid optimization of a peptide inhibitor of malaria parasite invasion by comprehensive N-methyl scanning. J Biol Chem 284 9361 9371

72. RichardDMacRaildCARiglarDTChanJAFoleyM 2010 Interaction between Plasmodium falciparum apical membrane antigen 1 and the rhoptry neck protein complex defines a key step in the erythrocyte invasion process of malaria parasites. J Biol Chem 285 14815 14822

73. KockenCHvan der WelAMDubbeldMANarumDLvan de RijkeFM 1998 Precise timing of expression of a Plasmodium falciparum-derived transgene in Plasmodium berghei is a critical determinant of subsequent subcellular localization. J Biol Chem 273 15119 15124

74. UrbanS 2010 Taking the plunge: integrating structural, enzymatic and computational insights into a unified model for membrane-immersed rhomboid proteolysis. Biochem J 425 501 512

75. WatersAPThomasAWDeansJAMitchellGHHudsonDE 1990 A merozoite receptor protein from Plasmodium knowlesi is highly conserved and distributed throughout Plasmodium. J Biol Chem 265 17974 17979

76. GanttSPerssonCRoseKBirkettAJAbagyanR 2000 Antibodies against thrombospondin-related anonymous protein do not inhibit Plasmodium sporozoite infectivity in vivo. Infect Immun 68 3667 3673

77. BlackmanMJ 1994 Purification of Plasmodium falciparum merozoites for analysis of the processing of merozoite surface protein-1. Methods Cell Biol 45 213 220

78. DelplacePDubremetzJFFortierBVernesA 1985 A 50 kilodalton exoantigen specific to the merozoite release-reinvasion stage of Plasmodium falciparum. Mol Biochem Parasitol 17 239 251

79. BlackmanMJWhittleHHolderAA 1991 Processing of the Plasmodium falciparum major merozoite surface protein-1: identification of a 33-kilodalton secondary processing product which is shed prior to erythrocyte invasion. Mol Biochem Parasitol 49 35 44

80. Silmon de MonerriNCFlynnHRCamposMGHackettFKoussisK 2011 Global Identification of Multiple Substrates for PfSUB1, an Essential Malarial Processing Protease. Infect Immun 79 1086 1097