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MJD and OTU deubiquitinating enzymes in Schistosoma mansoni

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Abstract

The ubiquitination and deubiquitination of proteins can alter diverse cellular processes, such as proteolysis, trafficking, subcellular localisation, DNA repair, apoptosis and signal transduction. Deubiquitinating enzymes (DUBs) are responsible for removing ubiquitin from their target proteins. Previous reports have shown the presence of two subfamilies of DUBs in Schistosoma mansoni: Ub carboxyl-terminal hydrolase (UCH) and Ub-specific protease (USP). In this study, we analysed the ovarian tumour (OTU) and Machado-Joseph disease protein domain (MJD) proteases found in the Schistosoma mansoni genome database. An in silico analysis identified two different MJD subfamily members, SmAtaxin-3 and SmJosephin, and five distinct OTU proteases, SmOTU1, SmOTU3, SmOTU5a, SmOTU6b and SmOtubain. The phylogenetic analysis showed the evolutionary conservation of these proteins. Furthermore, the 3D structures confirmed the similarity of these proteins with human proteins. In addition, we performed quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and observed distinct expression profiles for all of the investigated transcripts between the cercariae, schistosomula and adult worm stages. Taken together, our data suggest that MJD and OTU subfamily members contribute to regulating the activity of the Ub-proteasome system during the life cycle of this parasite.

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References

  • Basch P, DiConza J (1977) In vitro development of Schistosoma mansoni cercariae. J Parasitol 63:245–249

    Article  CAS  PubMed  Google Scholar 

  • Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, Kiefer F, Cassarino TG, Bertoni M, Bordoli L, Schwede T (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42(Web Server issue):W252–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Blackford AN, Stewart GS (2010) When cleavage is not attractive: non-catalytic inhibition of ubiquitin chains at DNA double-strand breaks by OTUB1. DNA Repair (Amst) 10(2):245–9

    Article  Google Scholar 

  • Borodovsky A, Ovaa H, Kolli N, Gan-Erdene T, Wilkinson KD, Ploegh HL, Kessler BM (2002) Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family. Chem Biol 10:1149–59

  • Callis J (2014) The ubiquitination machinery of the ubiquitin system. Arabidopsis Book 12, e0174

    Article  PubMed Central  PubMed  Google Scholar 

  • Castro-Borges W, Cartwright J, Ashton PD, Braschi S, Guerra-Sá R, Rodrigues V, Wilson RA, Curwen RS (2007) The 20S proteasome of Schistosoma mansoni: a proteomic analysis. Proteomics 7:1065–1075

    Article  CAS  PubMed  Google Scholar 

  • Clague MJ, Barsukov I, Coulson JM, Liu H, Rigden DJ, Urbé S (2013) Deubiquitylases from genes to organism. Physiol Rev 93(3):1289–315

    Article  CAS  PubMed  Google Scholar 

  • Eletr ZM, Wilkinson KD (2014) Regulation of proteolysis by human deubiquitinating enzymes. Biochim Biophys Acta 1843(1):114–28

    Article  CAS  PubMed  Google Scholar 

  • Faesen AC, Luna-Vargas MPA, Geurink PP, Clerici M, Merkx R, van Dijk WJ, Hameed DS, El Oualid F, Ovaa H, Sixma TK (2011) The differential modulation of USP activity by internal regulatory domains, interactors and eight ubiquitin chain types. Chem Biol 18:1550–1561

    Article  CAS  PubMed  Google Scholar 

  • Ferro A, Carvalho AL, Teixeira-Castro A, Almeida C, Tomé RJ, Cortes L, Rodrigues AJ, Logarinho E, Sequeiros J, Macedo-Ribeiro S, Maciel P (2007) NEDD8: a new ataxin-3 interactor. Biochim Biophys Acta 1773(11):1619–27

    Article  CAS  PubMed  Google Scholar 

  • Fishelson Z, Amiri P, Friend DS, Marikovsky M, Petitt M, Newport G, McKerrow JH (1992) Schistosoma mansoni: cell-specific expression and secretion of a serine protease during development of cercariae. Exp Parasitol 75:87–98

    Article  CAS  PubMed  Google Scholar 

  • Guerra-Sá R, Castro-Borges W, Evangelista EA, Kettelhut IC, Rodrigues V (2005) Schistosoma mansoni: functional proteasomes are required for development in the vertebrate host. Exp Parasitol 109:228–236

    Article  PubMed  Google Scholar 

  • Harrop R, Wilson RA (1993) Protein synthesis and release by cultured schistosomula of Schistosoma mansoni. Parasitology 107:265–274

    Article  CAS  PubMed  Google Scholar 

  • Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–79

    Article  CAS  PubMed  Google Scholar 

  • Ju HL, Kang JM, Noh HS, Kim DR, Hong Y, Sohn WM, Na BK (2014) Characterization of a novel otubain-like cysteine protease of Cryptosporidium parvum. Parasitol Int 63(4):580–3

    Article  CAS  PubMed  Google Scholar 

  • Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM (2007) DUBA: a deubiquitinase that regulates type I interferon production. Science 318:1628–1632

    Article  CAS  PubMed  Google Scholar 

  • Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563

    Article  CAS  PubMed  Google Scholar 

  • Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–8

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Sun XX, Elferich J, Shinde U, David LL, Dai MS (2014) Monoubiquitination is critical for ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (Otub1) to suppress UbcH5 enzyme and stabilize p53 protein. J Biol Chem 289(8):5097–108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Liu S, Cai P, Hou N, Piao X, Wang H, Hung T, Chen Q (2012) Genome-wide identification and characterization of a panel of house-keeping genes in Schistosoma japonicum. Mol Biochem Parasitol 182(1-2):75–82

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta DeltaC(T)) Method”. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Makarova KS, Aravind L, Koonin EV (2000) A novel superfamily of predicted cysteine proteases from eukaryotes, viruses and Chlamydia pneumoniae. Trends Biochem Sci 25:50–2

    Article  CAS  PubMed  Google Scholar 

  • Masino L, Nicastro G, De Simone A, Calder L, Molloy J, Pastore A (2011) The Josephin domain determines the morphological and mechanical properties of ataxin-3 fibrils. Biophys J 100(8):2033–42

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McGouran JF, Gaertner SR, Altun M, Kramer HB, Kessler BM (2013) Deubiquitinating enzyme specificity for ubiquitin chain topology profiled by di-ubiquitin activity probes. Chem Biol 20(12):1447–55

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McKerrow JH, Salter J (2002) Invasion of skin by Schistosoma cercariae. Trends Parasitol 18:193–195

    Article  PubMed  Google Scholar 

  • McNicholas S, Potterton, Wilson KS, Noble ME (2011) Presenting your structures: the CCP4mg molecular-graphics software. Acta Crystallogr D Biol Crystallogr 67(Pt 4):386–94

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Messick TE, Russell NS, Iwata AJ, Sarachan KL, Shiekhattar R, Shanks JR, Reyes-Turcu FE, Wilkinson KD, Marmorstein R (2008) Structural basis for ubiquitin recognition by the Otu1 ovarian tumor domain protein. J Biol Chem 283(16):11038–49

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H, Komander D (2013) OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell 154(1):169–84

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O’Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras AC, Natsume T, Suda T, Durocher D (2010) Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature 466(7309):941–6

    Article  CAS  PubMed  Google Scholar 

  • Nicastro G, Masino L, Esposito V, Menon RP, De Simone A, Fraternali F, Pastore A (2009) Josephin domain of ataxin-3 contains two distinct ubiquitin-binding sites. Biopolymers 91(12):1203–14

    Article  CAS  PubMed  Google Scholar 

  • Nicastro G, Menon RP, Masino L, Knowles PP, McDonald NQ, Pastore A (2005) The solution structure of the Josephin domain of ataxin-3: structural determinants for molecular recognition. Proc Natl Acad Sci U S A 102(30):10493–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pereira RV, Vieira HG, Oliveira VF, Gomes MD, Passos LK, Borges WD, Guerra-Sá R (2014) Conservation and developmental expression of ubiquitin isopeptidases in Schistosoma mansoni. Mem Inst Oswaldo Cruz 109(1):1–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rawlings ND, Barrett AJ, Bateman A (2010) MEROPS: the peptidase database. Nucleic Acids Res 38:227–233

    Article  Google Scholar 

  • Rawlings ND, Morton FR, Kok CY, Kong J, Barrett AJ (2008) MEROPS: the peptidase database. Nucleic Acids Res 36:320–325

    Article  Google Scholar 

  • Reina CP, Zhong X, Pittman RN (2010) Proteotoxic stress increases nuclear localization of ataxin-3. Hum Mol Genet 19(2):235–49

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reyes-Turcu FE, Wilkinson KD (2009) Polyubiquitin binding and disassembly by deubiquitinating enzymes. Chem Rev 109:1495–1508

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    CAS  PubMed  Google Scholar 

  • Sato Y, Yamagata A, Goto-Ito S, Kubota K, Miyamoto R, Nakada S, Fukai S (2012) Molecular basis of Lys-63-linked polyubiquitination inhibition by the interaction between human deubiquitinating enzyme OTUB1 and ubiquitin-conjugating enzyme UBC13. J Biol Chem 287(31):25860–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Seki T, Gong L, Williams AJ, Sakai N, Todi SV, Paulson HL (2013) JosD1, a membrane-targeted deubiquitinating enzyme, is activated by ubiquitination and regulates membrane dynamics, cell motility, and endocytosis. J Biol Chem 288(24):17145–55

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stirewalt MA (1974) Schistosoma mansoni: cercaria to schistosomule. Adv Parasitol 12:115–182

    Article  CAS  PubMed  Google Scholar 

  • Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5. Molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28(10):2731–9

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tzvetkov N, Breuer P (2007) Josephin domain-containing proteins from a variety of species are active de-ubiquitination enzymes. Biol Chem 388(9):973–8

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Zheng Y, Zhu Y, Kong X, Hu L (2011) Evidence for OTUD-6B participation in B lymphocytes cell cycle after cytokine stimulation. PLoS One 6(1), e14514

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Weeks SD, Grasty KC, Hernandez-Cuebas L, Loll PJ (2011) Crystal structure of a Josephin-ubiquitin complex: evolutionary restraints on ataxin-3 deubiquitinating activity. J Biol Chem 286(6):4555–65

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wiener R, Zhang X, Wang T, Wolberger C (2012) The mechanism of OTUB1-mediated inhibition of ubiquitination. Nature 483(7391):618–22

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, Cohen RE, Peng J, Paulson HL (2008) The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283(39):26436–43

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors thank the following transcriptome initiatives: the São Paulo Transcriptome Consortium, the Minas Gerais Genome Network and the Wellcome Trust Genome Initiative (UK). This work was supported by the following Brazilian research agencies: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG, CBB - APQ-02101-11), Núcleo de Bioinformática da Universidade Federal de Ouro Preto (NuBio UFOP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

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Correspondence to Renata Guerra-Sá.

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Figure S1

Model of the predicted tertiary structures based on template proteins deposited in theSWISS-MODEL server(Biasiniet al. 2014). The structures were visualized using CCP4mg in cartoon format.A) SmAtaxin, B) SmJosephin, C) SmOtub, D) SmOTU1, E) SmOTU3, F) SmOTU5a, and G) SmOTU6b (GIF 102 kb)

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Pereira, R.V., de Souza Gomes, M., Costa, M.P. et al. MJD and OTU deubiquitinating enzymes in Schistosoma mansoni . Parasitol Res 114, 2835–2843 (2015). https://doi.org/10.1007/s00436-015-4484-1

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