Modulation of the Surface Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes
The mechanisms by which pathogens interact with their environment are of major importance, both for fulfilling the basic needs of the parasite and understanding immune evasion. For African trypanosomes, the surface is dominated by the variant surface glycoprotein (VSG), but recent data has demonstrated an important role for ubiquitylation in mediating turnover of invariant surface glycoproteins (ISGs) and maintaining ISG copy number independent of VSG. Further, ISG expression is required for suramin-sensitivity. Here we describe mechanisms mediating ISG turnover, uncovered using a screen for genes involved in sensitivity to suramin. These involve multiple aspects of the ubiquitylation machinery, and connect ISG turnover with additional surface proteins. Our data provide a first insight into the complexity of regulation of the ISG family, identifying further aspects to the control of a drug-sensitivity pathway in trypanosomes, and offering insights into metabolism of the parasite surface proteome.
Vyšlo v časopise:
Modulation of the Surface Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes. PLoS Pathog 11(10): e32767. doi:10.1371/journal.ppat.1005236
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1005236
Souhrn
The mechanisms by which pathogens interact with their environment are of major importance, both for fulfilling the basic needs of the parasite and understanding immune evasion. For African trypanosomes, the surface is dominated by the variant surface glycoprotein (VSG), but recent data has demonstrated an important role for ubiquitylation in mediating turnover of invariant surface glycoproteins (ISGs) and maintaining ISG copy number independent of VSG. Further, ISG expression is required for suramin-sensitivity. Here we describe mechanisms mediating ISG turnover, uncovered using a screen for genes involved in sensitivity to suramin. These involve multiple aspects of the ubiquitylation machinery, and connect ISG turnover with additional surface proteins. Our data provide a first insight into the complexity of regulation of the ISG family, identifying further aspects to the control of a drug-sensitivity pathway in trypanosomes, and offering insights into metabolism of the parasite surface proteome.
Zdroje
1. Barrett MP, Vincent IM, Burchmore RJ, Kazibwe AJ, Matovu E. Drug resistance in human African trypanosomiasis. Future Microbiol. 2011; 6(9): 1037–1047. doi: 10.2217/fmb.11.88 21958143
2. Desquesnes M, Holzmuller P, Lai DH, Dargantes A, Lun ZR, Jittaplapong S. Trypanosoma evansi and surra: a review and perspectives on origin, history, distribution, taxonomy, morphology, hosts, and pathogenic effects. Biomed Res Int. 2013; 2013: 194176. doi: 10.1155/2013/194176 24024184
3. Field MC, Carrington M. The trypanosome flagellar pocket. Nat. Rev. Microbiol. 2009; 7:775–786. doi: 10.1038/nrmicro2221 19806154
4. Morrison LJ, Marcello L, McCulloch R. Antigenic variation in the African trypanosome: molecular mechanisms and phenotypic complexity. Cell Microbiol. 2009; 11: 1724 Micro doi: 10.1111/j.1462-5822.2009.01383.x 19751359
5. Ziegelbauer K, Overath P. Identification of invariant surface glycoproteins in the bloodstream stage of Trypanosoma brucei. J Biol Chem. 1992; 267(15): 10791–10796. 1587855
6. Gadelha C, Zhang W, Chamberlain JW, Chait BT, Wickstead B, Field MC. Architecture of a host-parasite interface: complex targeting mechanisms revealed through proteomics. Mol Cell Proteomics. 2015; 14(7):1911–1926 doi: 10.1074/mcp.M114.047647 25931509
7. Chung WL, Leung KF, Carrington M, Field MC. Ubiquitylation is required for degradation of transmembrane surface proteins in trypanosomes. Traffic. 2008; 9(10): 1681–1697. doi: 10.1111/j.1600-0854.2008.00785.x 18657071
8. Leung KF, Riley FS, Carrington M, Field MC. Ubiquitylation and developmental regulation of invariant surface protein expression in trypanosomes. Eukaryot Cell. 2011; 10(7): 916–931. doi: 10.1128/EC.05012-11 21571921
9. Henne WM, Buchkovich NJ, Emr SD. The ESCRT pathway. Dev Cell. 2011; 21(1): 77–91. doi: 10.1016/j.devcel.2011.05.015 21763610
10. Leung KF, Dacks JB, Field MC. Evolution of the multivesicular body ESCRT machinery; retention across the eukaryotic lineage. Traffic. 2008; 9(10): 1698–716. doi: 10.1111/j.1600-0854.2008.00797.x 18637903
11. Alsford S, Eckert S, Baker N, Glover L, Sanchez-Flores A, Leung KF, et al. High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature. 2012; 482: 232–236. doi: 10.1038/nature10771 22278056
12. Steverding D. The development of drugs for treatment of sleeping sickness: a historical review. Parasit Vectors. 2010; 3(1): 15. doi: 10.1186/1756-3305-3-15 20219092
13. Marger MD, Saier MH Jr. A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport. Trends Biochem Sci. 1993; 18(1):13–20. 8438231
14. Allen CL, Liao D, Chung WL, Field MC. Dileucine signal-dependent and AP-1-independent targeting of a lysosomal glycoprotein in Trypanosoma brucei. Mol Biochem Parasitol. 2007; 156(2): 175–190. 17869353
15. Lingnau A, Zufferey R, Lingnau M, Russell DG. Characterization of tGLP-1, a Golgi and lysosome-associated, transmembrane glycoprotein of African trypanosomes. J Cell Sci. 1999; 112 Pt 18: 3061–3070. 10462522
16. Koumandou VL, Klute MJ, Herman EK, Nunez-Miguel R, Dacks JB, Field MC. Evolutionary reconstruction of the retromer complex and its function in Trypanosoma brucei. J Cell Sci. 2011; 124(Pt 9): 1496–1509. doi: 10.1242/jcs.081596 21502137
17. Caffrey CR, Hansell E, Lucas KD, Brinen LS, Alvarez Hernandez A, Cheng J, et al. Active site mapping, biochemical properties and subcellular localization of rhodesain, the major cysteine protease of Trypanosoma brucei rhodesiense. Mol Biochem Parasitol. 2001; 118(1): 61–73. 11704274
18. Steverding D, Sexton DW, Wang X, Gehrke SS, Wagner GK, Caffrey CR. Trypanosoma brucei: chemical evidence that cathepsin L is essential for survival and a relevant drug target. Int J Parasitol. 2012; 42(5): 481–488. doi: 10.1016/j.ijpara.2012.03.009 22549023
19. Brickman MJ, Balber AE. Trypanosoma brucei rhodesiense: membrane glycoproteins localized primarily in endosomes and lysosomes of bloodstream forms. Exp Parasitol. 1993 Jun; 76(4): 329–344. 7685707
20. Peck RF, Shiflett AM, Schwartz KJ, McCann A, Hajduk SL, Bangs JD. The LAMP-like protein p67 plays an essential role in the lysosome of African trypanosomes. Mol Microbiol. 2008; 68(4): 933–946. doi: 10.1111/j.1365-2958.2008.06195.x 18430083
21. Hirst J, Borner GH, Antrobus R, Peden AA, Hodson NA, Sahlender DA, et al. Distinct and overlapping roles for AP-1 and GGAs revealed by the "knocksideways" system. Curr Biol. 2012; 22(18): 1711–1716. doi: 10.1016/j.cub.2012.07.012 22902756
22. Tazeh NN, Silverman JS, Schwartz KJ, Sevova ES, Sutterwala SS, Bangs JD. Role of AP-1 in developmentally regulated lysosomal trafficking in Trypanosoma brucei. Eukaryot Cell. 2009; 8(9): 1352–1361. doi: 10.1128/EC.00156-09 19581441
23. Manna PT, Kelly S, Field MC. Adaptin evolution in kinetoplastids and emergence of the variant surface glycoprotein coat in African trypanosomatids. Mol Phylogenet Evol. 2013; 67(1): 123–128. doi: 10.1016/j.ympev.2013.01.002 23337175
24. Willson M, Callens M, Kuntz DA, Perié J, Opperdoes FR. Synthesis and activity of inhibitors highly specific for the glycolytic enzymes from Trypanosoma brucei. Mol Biochem Parasitol. 1993; 59(2): 201–210. 8341319
25. Morgan HP, McNae IW, Nowicki MW, Zhong W, Michels PA, Auld DS, et al. The trypanocidal drug suramin and other trypan blue mimetics are inhibitors of pyruvate kinases and bind to the adenosine site. J Biol Chem. 2011; 286(36): 31232–31240. doi: 10.1074/jbc.M110.212613 21733839
26. Alsford S, Field MC, Horn D. Receptor-mediated endocytosis for drug delivery in African trypanosomes: fulfilling Paul Ehrlich’s vision of chemotherapy. Trends Parasitol. 2013; 29(5): 207–212. doi: 10.1016/j.pt.2013.03.004 23601931
27. Silverman JS, Muratore KA, Bangs JD. Characterization of the Late Endosomal ESCRT Machinery in Trypanosoma brucei. Traffic. 2013; 14(10): 1078–1090. doi: 10.1111/tra.12094 23905922
28. Nicholson B, Suresh Kumar KG. The multifaceted roles of USP7: new therapeutic opportunities. Cell Biochem Biophys. 2011; 60(1–2): 61–8. doi: 10.1007/s12013-011-9185-5 21468693
29. Li Z, Na X, Wang D, Schoen SR, Messing EM, Wu G. Ubiquitination of a novel deubiquitinating enzyme requires direct binding to von Hippel-Lindau tumor suppressor protein. J Biol Chem. 2002; 277(7): 4656–4662. 11739384
30. Allen CL, Goulding D, Field MC. Clathrin-mediated endocytosis is essential in Trypanosoma brucei. EMBO J. 2003; 22(19): 4991–5002. 14517238
31. Hall B, Allen CL, Goulding D, Field MC. Both of the Rab5 subfamily small GTPases of Trypanosoma brucei are essential and required for endocytosis. Mol Biochem Parasitol. 2004 Nov; 138(1): 67–77. 15500917
32. Adung'a VO, Gadelha C, Field MC. Proteomic analysis of clathrin interactions in trypanosomes reveals dynamic evolution of endocytosis. Traffic. 2013; 14(4): 440–457. doi: 10.1111/tra.12040 23305527
33. Engstler M, Weise F, Bopp K, Grünfelder CG, Günzel M, Heddergott N, et al. The membrane-bound histidine acid phosphatase TbMBAP1 is essential for endocytosis and membrane recycling in Trypanosoma brucei. J Cell Sci. 2005; 118(Pt 10): 2105–2118. 15855239
34. Salmon D, Geuskens M, Hanocq F, Hanocq-Quertier J, Nolan D, Ruben L et al. A novel heterodimeric transferrin receptor encoded by a pair of VSG expression site-associated genes in T. brucei. Cell. 1994; 78(1):75–86. 8033214
35. Steverding D, Stierhof YD, Chaudhri M, Ligtenberg M, Schell D, Beck-Sickinger AG et al. ESAG 6 and 7 products of Trypanosoma brucei form a transferrin binding protein complex. Eur J Cell Biol. 1994; 64(1): 78–87. 7957316
36. Gluenz E, Barker AR, Gull K. An expanded family of proteins with BPI/LBP/PLUNC-like domains in trypanosome parasites: an association with pathogenicity? Biochem Soc Trans. 2011; 39(4): 966–970. doi: 10.1042/BST0390966 21787331
37. Barker AR, Wickstead B, Gluenz E, Gull K. Bioinformatic insights to the ESAG5 and GRESAG5 gene families in kinetoplastid parasites. Mol Biochem Parasitol. 2008; 162(2): 112–122. doi: 10.1016/j.molbiopara.2008.08.003 18773926
38. Mussmann R, Engstler M, Gerrits H, Kieft R, Toaldo CB, Onderwater J, et al. Factors affecting the level and localization of the transferrin receptor in Trypanosoma brucei. J Biol Chem. 2004; 279(39): 40690–40698. 15263009
39. Krogh BL, von Heijne G, Sonnhammer ELL. Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes. J. Mol. Biol., 2001; 305(3):567–580.
40. Bendtsen JD, Nielsen H, von Heijne G, Brunak S. Improved prediction of signal peptides: SignalP 3.0. J. Mol. Biol., 2004; 340: 783–795.
41. Pierleoni A, Martelli PL, Casadio R. PredGPI: a GPI anchor predictor. BMC Bioinformatics. 2008; 9: 392 doi: 10.1186/1471-2105-9-392 18811934
42. Karpenahalli MR, Lupas AN, Söding J. TPRpred: a tool for prediction of TPR-, PPR- and SEL1-like repeats from protein sequences. BMC Bioinformatics. 2007; 8:2. 17199898
43. Manna PT, Boehm C, Leung KF, Natesan SK, Field MC, Life and times: synthesis, trafficking, and evolution of VSG. Trends Parasitol. 2014; 30(5): 251–258. doi: 10.1016/j.pt.2014.03.004 24731931
44. Alexander DL, Schwartz KJ, Balber AE, Bangs JD. Developmentally regulated trafficking of the lysosomal membrane protein p67 in Trypanosoma brucei. J Cell Sci. 2002;115(Pt 16): 3253–3263. 12140257
45. Radivojac P, Vacic V, Haynes C, Cocklin RR, Mohan A, Heyen JW et al. Identification, analysis, and prediction of protein ubiquitination sites. Proteins. 2010; 78(2): 365–380. doi: 10.1002/prot.22555 19722269
46. Koumandou VL, Klute MJ, Herman EK, Nunez-Miguel R, Dacks JB, Field MC. Evolutionary reconstruction of the retromer complex and its function in Trypanosoma brucei. J Cell Sci. 2011; 124(Pt 9): 1496–1509. doi: 10.1242/jcs.081596 21502137
47. Koumandou VL, Boehm C, Horder KA, Field MC. Evidence for recycling of invariant surface trans-membrane domain proteins in African trypanosomes. Eukaryot Cell. 2013;12(2):330–342. doi: 10.1128/EC.00273-12 23264644
48. Grau-Bove X, Sebe-Pedros A, Ruiz-Trillo I. The Eukaryotic Ancestor Had a Complex Ubiquitin Signaling System of Archaeal Origin. Molecular Biology and Evolution. 2015 13;32(3):726–739. doi: 10.1093/molbev/msu334 25525215
49. Komander D, Clague MJ, Urbé S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009; 10(8): 550–563. doi: 10.1038/nrm2731 19626045
50. Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW, et al. Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. J Clin Invest. 2003; 112(2): 189–196. 12865408
51. Frearson JA, Brand S, McElroy SP, Cleghorn LA, Smid O, Stojanovski L, et al. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness.Nature. 2010; 464(7289): 728–732. doi: 10.1038/nature08893 20360736
52. Hirumi H, Hirumi K. Axenic culture of African trypanosome bloodstream forms. Parasitol Today. 1994; 10(2): 80–84. 15275508
53. Alsford S, Kawahara T, Glover L, Horn D. Tagging a T. brucei RRNA locus improves stable transfection efficiency and circumvents inducible expression position effects. Mol Biochem Parasitol. 2005; 144(2): 142–148.
54. Alsford S, Horn D. Single-locus targeting constructs for reliable regulated RNAi and trans-gene expression in Trypanosoma brucei. Mol Biochem Parasitol. 2008; 161(1): 76–79 doi: 10.1016/j.molbiopara.2008.05.006 18588918
55. Redmond S, Vadivelu J, Field MC. RNAit: an automated web-based tool for the selection of RNAi targets in Trypanosoma brucei. Mol Biochem Parasitol. 2004; 128(1):115–118.
56. Koumandou VL, Natesan SK, Sergeenko T, Field MC. The trypanosome transcriptome is remodelled during differentiation but displays limited responsiveness within life stages. BMC Genomics. 2008; 9: 298. doi: 10.1186/1471-2164-9-298 18573209
57. Allison H, O’Reilly AJ, Sternberg J, Field MC. An extensive endoplasmic reticulum-localised glycoprotein family in trypanosomatids. Microbial Cell. 2014; 1(10): 325–345. 26167471
58. Urbaniak MD, Guther ML, Ferguson MA (2012) Comparative SILAC proteomic analysis of Trypanosoma brucei bloodstream and procyclic lifecycle stages. PLoS One. 2012; 7(5): e36619. doi: 10.1371/journal.pone.0036619 22574199
59. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008; 26: 1367–1372. doi: 10.1038/nbt.1511 19029910
60. Aslett M, Aurrecoechea C, Berriman M, Brestelli J, Brunk BP, Carrington M, et al. TriTrypDB: a functional genomic resource for the Trypanosomatidae. Nucleic Acid Res. 2010; 38: D457–D462. doi: 10.1093/nar/gkp851 19843604
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2015 Číslo 10
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Chronobiomics: The Biological Clock as a New Principle in Host–Microbial Interactions
- Interferon-γ: The Jekyll and Hyde of Malaria
- Crosslinking of a Peritrophic Matrix Protein Protects Gut Epithelia from Bacterial Exotoxins
- Modulation of the Surface Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes