Transgenic Analysis of the MAP Kinase MPK10 Reveals an Auto-inhibitory Mechanism Crucial for Stage-Regulated Activity and Parasite Viability
Leishmaniasis is an important human disease caused by Leishmania parasites. A crucial aspect of Leishmania infectivity is its capacity to sense different environments and adapt for survival inside insect vector and vertebrate host by stage differentiation. This process is triggered by environmental changes encountered in these organisms, including temperature and pH shifts, which usually are sensed and transduced by signaling cascades including protein kinases and their substrates. In this study, we analyzed the regulation of the Leishmania mitogen-activated protein kinase MPK10 using protein purified from transgenic parasites and combining site-directed mutagenesis and activity tests. We demonstrate that this kinase is activated during parasite differentiation and regulated by an atypical mechanism involving auto-inhibition, which is essential for parasite viability.
Vyšlo v časopise:
Transgenic Analysis of the MAP Kinase MPK10 Reveals an Auto-inhibitory Mechanism Crucial for Stage-Regulated Activity and Parasite Viability. PLoS Pathog 10(9): e32767. doi:10.1371/journal.ppat.1004347
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004347
Souhrn
Leishmaniasis is an important human disease caused by Leishmania parasites. A crucial aspect of Leishmania infectivity is its capacity to sense different environments and adapt for survival inside insect vector and vertebrate host by stage differentiation. This process is triggered by environmental changes encountered in these organisms, including temperature and pH shifts, which usually are sensed and transduced by signaling cascades including protein kinases and their substrates. In this study, we analyzed the regulation of the Leishmania mitogen-activated protein kinase MPK10 using protein purified from transgenic parasites and combining site-directed mutagenesis and activity tests. We demonstrate that this kinase is activated during parasite differentiation and regulated by an atypical mechanism involving auto-inhibition, which is essential for parasite viability.
Zdroje
1. AlvarJ, VélezID, BernC, HerreroM, DesjeuxP, et al. (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS One 7: e35671.
2. ZilbersteinD, ShapiraM (1994) The role of pH and temperature in the development of Leishmania parasites. Annu Rev Microbiol 48: 449–470.
3. DoylePS, EngelJC, PimentaPF, da SilvaPP, DwyerDM (1991) Leishmania donovani: long-term culture of axenic amastigotes at 37 degrees C. Exp Parasitol 73: 326–334.
4. GoyardS, SegawaH, GordonJ, ShowalterM, DuncanR, et al. (2003) An in vitro system for developmental and genetic studies of Leishmania donovani phosphoglycans. Mol Biochem Parasitol 130: 31–42.
5. KültzD (1998) Phylogenetic and functional classification of mitogen- and stress-activated protein kinases. J Mol Evol 46: 571–588.
6. HindleyA, KolchW (2002) Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases. J Cell Sci 115: 1575–1581.
7. FerrellJEJr, BhattRR (1997) Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase. J Biol Chem 272: 19008–19016.
8. DavisRJ (1995) Transcriptional regulation by MAP kinases. Mol Reprod Dev 42: 459–467.
9. CargnelloM, RouxPP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75: 50–83.
10. ChengM, SexlV, SherrCJ, RousselMF (1998) Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc Natl Acad Sci U S A 95: 1091–1096.
11. WrightJH, MunarE, JamesonDR, AndreassenPR, MargolisRL, et al. (1999) Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts. Proc Natl Acad Sci U S A 96: 11335–11340.
12. BrooksDR, McCullochR, CoombsGH, MottramJC (2000) Stable transformation of trypanosomatids through targeted chromosomal integration of the selectable marker gene encoding blasticidin S deaminase. FEMS Microbiol Lett 186: 287–291.
13. DeanJL, BrookM, ClarkAR, SaklatvalaJ (1999) p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem 274: 264–269.
14. ParryD, MahonyD, WillsK, LeesE (1999) Cyclin D-CDK subunit arrangement is dependent on the availability of competing INK4 and p21 class inhibitors. Mol Cell Biol 19: 1775–1783.
15. IvensAC, PeacockCS, WortheyEA, MurphyL, AggarwalG, et al. (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 30: 436–442.
16. WieseM (2007) Leishmania MAP kinases–familiar proteins in an unusual context. Int J Parasitol 37: 1053–1062.
17. ParsonsM, WortheyEA, WardPN, MottramJC (2005) Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genomics 6: 127.
18. WieseM (1998) A mitogen-activated protein (MAP) kinase homologue of Leishmania mexicana is essential for parasite survival in the infected host. EMBO J 17: 2619–2628.
19. WieseM, KuhnD, GrünfelderCG (2003) Protein kinase involved in flagellar-length control. Eukaryot Cell 2: 769–777.
20. BengsF, ScholzA, KuhnD, WieseM (2005) LmxMPK9, a mitogen-activated protein kinase homologue affects flagellar length in Leishmania mexicana. Mol Microbiol 55: 1606–1615.
21. KuhnD, WieseM (2005) LmxPK4, a mitogen-activated protein kinase kinase homologue of Leishmania mexicana with a potential role in parasite differentiation. Mol Microbiol 56: 1169–1182.
22. ErdmannM, ScholzA, MelzerIM, SchmetzC, WieseM (2006) Interacting protein kinases involved in the regulation of flagellar length. Mol Biol Cell 17: 2035–2045.
23. RotureauB, MoralesMA, BastinP, SpäthGF (2009) The flagellum-mitogen-activated protein kinase connection in Trypanosomatids: a key sensory role in parasite signalling and development? Cell Microbiol 11: 710–718.
24. MoralesMA, RenaudO, FaigleW, ShorteSL, SpäthGF (2007) Over-expression of Leishmania major MAP kinases reveals stage-specific induction of phosphotransferase activity. Int J Parasitol 37: 1187–1199.
25. MoralesMA, WatanabeR, LaurentC, LenormandP, RousselleJ-C, et al. (2008) Phosphoproteomic analysis of Leishmania donovani pro- and amastigote stages. Proteomics 8: 350–363.
26. MoralesMA, PescherP, SpäthGF (2010) Leishmania major MPK7 protein kinase activity inhibits intracellular growth of the pathogenic amastigote stage. Eukaryot Cell 9: 22–30.
27. von FreyendSJ, RosenqvistH, FinkA, MelzerIM, ClosJ, et al. (2010) LmxMPK4, an essential mitogen-activated protein kinase of Leishmania mexicana is phosphorylated and activated by the STE7-like protein kinase LmxMKK5. Int J Parasitol 40: 969–978.
28. KannanN, NeuwaldAF (2004) Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2alpha. Protein Sci 13: 2059–2077.
29. HorjalesS, Schmidt-ArrasD, LimardoRR, LeclercqO, ObalG, et al. (2012) The crystal structure of the MAP kinase LmaMPK10 from Leishmania major reveals parasite-specific features and regulatory mechanisms. Structure 20: 1649–1660.
30. ZhouG, BaoZQ, DixonJE (1995) Components of a new human protein kinase signal transduction pathway. J Biol Chem 270: 12665–12669.
31. LeeJD, UlevitchRJ, HanJ (1995) Primary structure of BMK1: a new mammalian map kinase. Biochem Biophys Res Commun 213: 715–724.
32. EllisJ, SarkarM, HendriksE, MatthewsK (2004) A novel ERK-like, CRK-like protein kinase that modulates growth in Trypanosoma brucei via an autoregulatory C-terminal extension. Mol Microbiol 53: 1487–1499.
33. AbeMK, KuoWL, HershensonMB, RosnerMR (1999) Extracellular signal-regulated kinase 7 (ERK7), a novel ERK with a C-terminal domain that regulates its activity, its cellular localization, and cell growth. Mol Cell Biol 19: 1301–1312.
34. AbeMK, KahleKT, SaelzlerMP, OrthK, DixonJE, et al. (2001) ERK7 is an autoactivated member of the MAPK family. J Biol Chem 276: 21272–21279.
35. KornevAP, HasteNM, TaylorSS, EyckLFT (2006) Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc Natl Acad Sci U S A 103: 17783–17788.
36. TaylorSS, KornevAP (2011) Protein kinases: evolution of dynamic regulatory proteins. Trends Biochem Sci 36: 65–77.
37. CobbMH, BoultonTG, RobbinsDJ (1991) Extracellular signal-regulated kinases: ERKs in progress. Cell Regul 2: 965–978.
38. VerlhacMH, KubiakJZ, ClarkeHJ, MaroB (1994) Microtubule and chromatin behavior follow MAP kinase activity but not MPF activity during meiosis in mouse oocytes. Development 120: 1017–1025.
39. KubiakJZ (2013) Protein kinase assays for measuring MPF and MAPK activities in mouse and rat oocytes and early embryos. Methods Mol Biol 957: 77–89.
40. RosenqvistH, YeJ, JensenON (2011) Analytical strategies in mass spectrometry-based phosphoproteomics. Methods Mol Biol 753: 183–213.
41. ProwseCN, LewJ (2001) Mechanism of activation of ERK2 by dual phosphorylation. J Biol Chem 276: 99–103.
42. RobbinsDJ, ZhenE, OwakiH, VanderbiltCA, EbertD, et al. (1993) Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J Biol Chem 268: 5097–5106.
43. CobbMH, GoldsmithEJ (1995) How MAP kinases are regulated. J Biol Chem 270: 14843–14846.
44. MoralesMA, WatanabeR, DacherM, ChafeyP, Osorio y FortéaJ, et al. (2010) Phosphoproteome dynamics reveal heat-shock protein complexes specific to the Leishmania donovani infectious stage. Proc Natl Acad Sci U S A 107: 8381–8386.
45. HuseM, KuriyanJ (2002) The conformational plasticity of protein kinases. Cell 109: 275–282.
46. CanagarajahBJ, KhokhlatchevA, CobbMH, GoldsmithEJ (1997) Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90: 859–869.
47. BellM, EngelbergD (2003) Phosphorylation of Tyr-176 of the yeast MAPK Hog1/p38 is not vital for Hog1 biological activity. J Biol Chem 278: 14603–14606.
48. JohnsonLN, NobleME, OwenDJ (1996) Active and inactive protein kinases: structural basis for regulation. Cell 85: 149–158.
49. EnglishJ, PearsonG, WilsbacherJ, SwantekJ, KarandikarM, et al. (1999) New insights into the control of MAP kinase pathways. Exp Cell Res 253: 255–270.
50. GonzalezJ, CornejoA, SantosMR, CorderoEM, GutierrezB, et al. (2003) A novel protein phosphatase 2A (PP2A) is involved in the transformation of human protozoan parasite Trypanosoma cruzi. Biochem J 374: 647–656.
51. BuschbeckM, UllrichA (2005) The unique C-terminal tail of the mitogen-activated protein kinase ERK5 regulates its activation and nuclear shuttling. J Biol Chem 280: 2659–2667.
52. HuSH, ParkerMW, LeiJY, WilceMC, BenianGM, et al. (1994) Insights into autoregulation from the crystal structure of twitchin kinase. Nature 369: 581–584.
53. BrondelloJM, PouyssegurJ, McKenzieFR (1999) Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286: 2514–2517.
54. NicholsA, CampsM, GillieronC, ChabertC, BrunetA, et al. (2000) Substrate recognition domains within extracellular signal-regulated kinase mediate binding and catalytic activation of mitogen-activated protein kinase phosphatase-3. J Biol Chem 275: 24613–24621.
55. SmithTG, SweetmanD, PattersonM, KeyseSM, MunsterbergA (2005) Feedback interactions between MKP3 and ERK MAP kinase control scleraxis expression and the specification of rib progenitors in the developing chick somite. Development 132: 1305–1314.
56. BreitwieserW, LyonsS, FlennikenAM, AshtonG, BruderG, et al. (2007) Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. Genes Dev 21: 2069–2082.
57. Cohen-FreueG, HolzerTR, ForneyJD, McMasterWR (2007) Global gene expression in Leishmania. Int J Parasitol 37: 1077–1086.
58. ModyN, CampbellDG, MorriceN, PeggieM, CohenP (2003) An analysis of the phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (ERK5) by mitogen-activated protein kinase kinase 5 (MKK5) in vitro. Biochem J 372 (Pt 2) 567–75.
59. SaarY, RansfordA, WaldmanE, MazarebS, Amin-SpectorS, et al. (1998) Characterization of developmentally-regulated activities in axenic amastigotes of Leishmania donovani. Mol Biochem Parasitol 95: 9–20.
60. DwyerDM (1976) Antibody-induced modulation of Leishmania donovani surface membrane antigens. J Immunol 117: 2081–2091.
61. MenzB, WinterG, IlgT, LottspeichF, OverathP (1991) Purification and characterization of a membrane-bound acid phosphatase of Leishmania mexicana. Mol Biochem Parasitol 47: 101–108.
62. LeBowitzJH (1994) Transfection experiments with Leishmania. Methods Cell Biol 45: 65–78.
63. AslettM, AurrecoecheaC, BerrimanM, BrestelliJ, BrunkBP, et al. (2010) TriTrypDB: a functional genomic resource for the Trypanosomatidae. Nucleic Acids Res 38: D457–462.
64. AltschulSF, MaddenTL, SchäfferAA, ZhangJ, ZhangZ, et al. (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25: 3389–3402.
65. JonassenI (1997) Efficient discovery of conserved patterns using a pattern graph. Comput Appl Biosci 13 (5) 509–522.
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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