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Nuclear transport in Entamoeba histolytica: knowledge gap and therapeutic potential

Published online by Cambridge University Press:  22 March 2018

Marina A. Gwairgi
Affiliation:
Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, Australia
Reena Ghildyal*
Affiliation:
Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, Australia
*
Author for correspondence: Reena Ghildyal, E-mail: [email protected]

Abstract

Entamoeba histolytica is the protozoan parasite that causes human amoebiasis. It is one of the leading parasitic disease burdens in tropical regions and developing countries, with spread to developed countries through migrants from and travellers to endemic regions.

Understanding E. histolytica’s invasion mechanisms requires an understanding of how it interacts with external cell components and how it engulfs and kills cells (phagocytosis). Recent research suggests that optimal phagocytosis requires signalling events from the cell surface to the nucleus via the cytoplasm, and the induction of several factors that are transported to the plasma membrane. Current research in other protozoans suggests the presence of proteins with nuclear localization signals, nuclear export signals and Ran proteins; however, there is limited literature on their functionality and their functional similarity to higher eukaryotes.

Based on learnings from the development of antivirals, nuclear transport elements in E. histolytica may present viable, specific, therapeutic targets.

In this review, we aim to summarize our limited knowledge of the eukaryotic nuclear transport mechanisms that are conserved and may function in E. histolytica.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2018 

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References

Aguilar-Diaz, H, Carrero, JC, Arguello-Garcia, R, Laclette, JP and Morales-Montor, J (2011) Cyst and encystment in protozoan parasites: optimal targets for new life-cycle interrupting strategies? Trends in Parasitology 27(10), 450458.Google Scholar
Al-Areeqi, MA, Sady, H, Al-Mekhlafi, HM, Anuar, TS, Al-Adhroey, AH, Atroosh, WM, Dawaki, S, Elyana, FN, Nasr, NA, Ithoi, I, Lau, YL and Surin, J (2017) First molecular epidemiology of Entamoeba histolytica, E. dispar and E. moshkovskii infections in Yemen: different species-specific associated risk factors. Tropical Medicine & International Health 22(4), 493504.Google Scholar
Aslam, S, Bhattacharya, S and Bhattacharya, A (2012) The calmodulin-like calcium binding protein EhCaBP3 of Entamoeba histolytica regulates phagocytosis and is involved in actin dynamics. PLoS Pathogens 8(12), e1003055.Google Scholar
Aurrecoechea, C, Barreto, A, Brestelli, J, Brunk, BP., Caler, EV, Fischer, S, Gajria, B, Gao, X, Gingle, A, Grant, G, Harb, OS, Heiges, M, Iodice, J, Kissinger, JC, Kraemer, ET, Li, W, Nayak, V, Pennington, C, Pinney, DF, Pitts, B, Roos, DS, Srinivasamoorthy, G, Stoeckert, CJ Jr, Treatman, C and Wang, H (2011) AmoebaDB and MicrosporidiaDB: functional genomic resources for Amoebozoa and Microsporidia species. Nuclear Acids Research 39(database issue), D612-9.Google Scholar
Avalos-Padilla, Y, Betanzos, A, Javier-Reyna, R, Garcia-Rivera, G, Chavez-Munguia, B, Lagunes-Guillen, A, Ortega, J and Orozco, E (2015) Ehvps32 Is a vacuole-associated protein involved in pinocytosis and phagocytosis of Entamoeaba histolytica. PLoS Pathogens 11(7), e1005079.Google Scholar
Banuelos, C, Garcia-Rivera, G, Lopez-Reyes, I, Mendoza, L, Gonzalez-Robles, A, Herranz, S, Vincent, O and Orozco, E (2012) EhADH112 is a Bro1 domain-containing protein involved in the Entamoeba histolytica multivesicular bodies pathway. Journal of Biomedicine & Biotechnology 2012, 657942.Google Scholar
Beck, M, Lucic, V, Forster, F, Baumeister, W and Medalia, O (2007) Snapshots of nuclear pore complexes in action captured by cryo-electron tomography. Nature 449(7162), 611615.Google Scholar
Becker, SM, Cho, KN, Guo, X, Fendig, K, Oosman, MN, Whitehead, R, Cohn, SM and Houpt, ER (2010) Epithelial cell apoptosis facilitates Entamoeba histolytica infection in the gut. American Journal of Pathology 176(3), 13161322.Google Scholar
Begum, S, Quach, J and Chadee, K (2015) Immune evasion mechanisms of Entamoeba histolytica: progression to disease. Frontiers in Microbiology 6, 1394.Google Scholar
Bercu, TE, Petri, WA and Behm, JW (2007) Amebic colitis: new insights into pathogenesis and treatment. Current Gastroenterology Reports 9(5), 429433.Google Scholar
Berninghausen, O and Leippe, M (1997) Necrosis versus apoptosis as the mechanism of target cell death induced by Entamoeba histolytica. Infection and Immunity 65(9), 36153621.Google Scholar
Betanzos, A, Javier-Reyna, R, Garcia-Rivera, G, Banuelos, C, Gonzalez-Mariscal, L, Schnoor, M and Orozco, E (2013) The EhCPADH112 complex of Entamoeba histolytica interacts with tight junction proteins occludin and claudin-1 to produce epithelial damage. PLoS ONE 8(6), e65100.Google Scholar
Bhattacharya, A, Padhan, N, Jain, R and Bhattacharya, S (2006) Calcium-binding proteins of Entamoeba histolytica. Archives of Medical Research 37(2), 221225.Google Scholar
Bi, X, Jones, T, Abbasi, F, Lee, H, Stultz, B, Hursh, DA and Mortin, MA (2005) Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells. Oncogene 24(56), 82298239.Google Scholar
Caly, L, Ghildyal, R and Jans, DA (2015) Respiratory virus modulation of host nucleocytoplasmic transport; target for therapeutic intervention? Frontiers in Microbiology 6, 848.Google Scholar
Christy, NC and Petri, WA Jr. (2011) Mechanisms of adherence, cytotoxicity and phagocytosis modulate the pathogenesis of Entamoeba histolytica. Future Microbiology 6(12), 15011519.Google Scholar
Cruz-Vera, J, Clara, L, Hernandez-Kelly, R, Alfredo Mendez, J, Perez-Salazar, E and Ortega, A (2003) Collagen-induced STAT family members activation in Entamoeba histolytica trophozoites. FEMS Microbiology Letters 229(2), 203209.Google Scholar
Cuevas, IC, Frasch, AC and D'Orso, I (2005) Insights into a CRM1-mediated RNA-nuclear export pathway in Trypanosoma cruzi. Molecular & Biochemical Parasitology 139(1), 1524.Google Scholar
Debnath, A, Akbar, MA, Mazumder, A, Kumar, S and Das, P (2005) Entamoeba histolytica: characterization of human collagen type I and Ca2+ activated differentially expressed genes. Experimental Parasitology 110(3), 214219.Google Scholar
Debnath, A, Parsonage, D, Andrade, RM, He, C, Cobo, ER, Hirata, K, Chen, S, Garcia-Rivera, G, Orozco, E, Martinez, MB, Gunatilleke, SS, Barrios, AM, Arkin, MR, Poole, LB, McKerrow, JH and Reed, SL (2012) A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target. Natural Medicines 18(6), 956960.Google Scholar
Degrasse, JA and Devos, D (2010) A functional proteomic study of the Trypanosoma brucei nuclear pore complex: an informatic strategy. Methods in Molecular Biology 673, 231238.Google Scholar
Eichinger, D (2001) A role for a galactose lectin and its ligands during encystment of Entamoeba. Journal of Eukaryotic Microbiology 48(1), 1721.Google Scholar
Erickson, ES, Mooren, OL, Moore, D, Krogmeier, JR and Dunn, RC (2006) The role of nuclear envelope calcium in modifying nuclear pore complex structure. Canadian Journal of Physiology and Pharmacology 84(3–4), 309318.Google Scholar
Faust, DM and Guillen, N (2012) Virulence and virulence factors in Entamoeba histolytica, the agent of human amoebiasis. Microbes and Infection 14(15), 14281441.Google Scholar
Feldherr, C, Akin, D, Littlewood, T and Stewart, M (2002) The molecular mechanism of translocation through the nuclear pore complex is highly conserved. Journal of Cell Science 115(Pt 14), 29973005.Google Scholar
Frankel, MB and Knoll, LJ (2008) Functional analysis of key nuclear trafficking components reveals an atypical Ran network required for parasite pathogenesis. Molecular Microbiology 70(2), 410420.Google Scholar
Frankel, MB and Knoll, LJ (2009) The ins and outs of nuclear trafficking: unusual aspects in apicomplexan parasites. DNA and Cell Biology 28(6), 277284.Google Scholar
Frankel, MB, Mordue, DG and Knoll, LJ (2007) Discovery of parasite virulence genes reveals a unique regulator of chromosome condensation 1 ortholog critical for efficient nuclear trafficking. Proceedings of the National Academy of Sciences USA 104(24), 1018110186.Google Scholar
Fraser, JE, Rawlinson, SM, Wang, C, Jans, DA and Wagstaff, KM (2014) Investigating dengue virus nonstructural protein 5 (NS5) nuclear import. Methods in Molecular Biology 1138, 301328.Google Scholar
Fukuzawa, M, Abe, T and Williams, JG (2003) The Dictyostelium prestalk cell inducer DIF regulates nuclear accumulation of a STAT protein by controlling its rate of export from the nucleus. Development 130(4), 797804.Google Scholar
Ginger, RS, Dalton, EC, Ryves, WJ, Fukuzawa, M, Williams, JG and Harwood, AJ (2000) Glycogen synthase kinase-3 enhances nuclear export of a Dictyostelium STAT protein. The EMBO Journal 19(20), 54835491.Google Scholar
Gonzales, ML, Dans, LF and Martinez, EG (2009) Antiamoebic drugs for treating amoebic colitis. Cochrane Database of Systematic Reviews 2009(2), CD006085.Google Scholar
Guttler, T and Gorlich, D (2011) Ran-dependent nuclear export mediators: a structural perspective. The EMBO Journal 30(17), 34573474.Google Scholar
Ha, S, Jeong, J, Oh, J, Rhee, S and Ham, SW (2018) A small organic molecule blocks EGFR transport into the nucleus by the nonclassical pathway resulting in repression of cancer invasion. Chembiochem 19(2), 131135.Google Scholar
Hailemariam, G, Kassu, A, Abebe, G, Abate, E, Damte, D, Mekonnen, E and Ota, F (2004) Intestinal parasitic infections in HIV/AIDS and HIV seronegative individuals in a teaching hospital, Ethiopia. Japanese Journal of Infectious Diseases 57(2), 4143.Google Scholar
Hanadate, Y, Saito-Nakano, Y, Nakada-Tsukui, K and Nozaki, T (2016) Endoplasmic reticulum-resident Rab8A GTPase is involved in phagocytosis in the protozoan parasite Entamoeba histolytica. Cellular Microbiology 18(10), 13581373.Google Scholar
Haque, R, Huston, CD, Hughes, M, Houpt, E and Petri, WA Jr (2003) Amebiasis. New England Journal of Medicine 348(16), 15651573.Google Scholar
Hung, CC, Chang, SY and Ji, DD (2012) Entamoeba histolytica infection in men who have sex with men. The Lancet Infectious Diseases 12(9), 729736.Google Scholar
Kimura, M, Nakamura, T and Nawa, Y (2007) Experience with intravenous metronidazole to treat moderate-to-severe amebiasis in Japan. American Journal of Tropical Medicine and Hygiene 77(2), 381385.Google Scholar
London, CA, Bernabe, LF, Barnard, S, Kisseberth, WC, Borgatti, A, Henson, M, Wilson, H, Jensen, K, Ito, D, Modiano, JF, Bear, MD, Pennell, ML, Saint-Martin, JR, McCauley, D, Kauffman, M and Shacham, S (2014) Preclinical evaluation of the novel, orally bioavailable selective inhibitor of nuclear export (SINE) KPT-335 in spontaneous canine cancer: results of a phase I study. PLoS ONE 9(2), e87585.Google Scholar
Lopez-Reyes, I, Garcia-Rivera, G, Banuelos, C, Herranz, S, Vincent, O, Lopez-Camarillo, C, Marchat, LA and Orozco, E (2010) Detection of the endosomal sorting complex required for transport in Entamoeba histolytica and characterization of the EhVps4 protein. Journal of Biomedicine & Biotechnology 2010, 890674.Google Scholar
Mahipal, A and Malafa, M (2016) Importins and exportins as therapeutic targets in cancer. Pharmacology & Therapeutics 164, 135143.Google Scholar
Marie, C and Petri, WA Jr. (2013) Amoebic dysentery. BMJ Clinical Evidence 2013, pii: 0918..Google Scholar
Martinez-Higuera, A, Salas-Casas, A, Calixto-Galvez, M, Chavez-Munguia, B, Perez-Ishiwara, DG, Ximenez, C and Rodriguez, MA (2013) Identification of calcium-transporting ATPases of Entamoeba histolytica and cellular localization of the putative SERCA. Experimental Parasitology 135(1), 7986.Google Scholar
Mitra, P, Gupta, ED, Sahar, T, Pandey, AK, Dangi, P, Reddy, KS, Chauhan, VS and Gaur, D (2016) Evidence for the nucleo-apical shuttling of a beta-catenin like Plasmodium falciparum armadillo repeat containing protein. PLoS ONE 11(2), e0148446.Google Scholar
Mooren, OL, Erickson, ES, Moore-Nichols, D and Dunn, RC (2004) Nuclear side conformational changes in the nuclear pore complex following calcium release from the nuclear membrane. Physical Biology 1(1–2), 125134.Google Scholar
Moran, P, Ramos, F, Ramiro, M, Curiel, O, Gonzalez, E, Valadez, A, Gomez, A, Garcia, G, Melendro, EI and Ximenez, C (2005) Entamoeba histolytica and/or Entamoeba dispar: infection frequency in HIV + /AIDS patients in Mexico city. Experimental Parasitology 110(3), 331334.Google Scholar
Moreno, H, Linford, AS, Gilchrist, CA and Petri, WA Jr (2010) Phospholipid-binding protein EhC2A mediates calcium-dependent translocation of transcription factor URE3-BP to the plasma membrane of Entamoeba histolytica. Eukaryotic Cell 9(5), 695704.Google Scholar
Mukherjee, AK, Das, K, Bhattacharya, MK, Nozaki, T and Ganguly, S (2010) Trend of Entamoeba histolytica infestation in Kolkata. Gut Pathogens 2(1), 12.Google Scholar
NIH (2017) ClinicalTrials.gov. from https://clinicaltrials.gov/ct2/home.Google Scholar
O'Reilly, AJ, Dacks, JB and Field, MC (2011) Evolution of the karyopherin-beta family of nucleocytoplasmic transport factors; ancient origins and continued specialization. PLoS ONE 6(4), e19308.Google Scholar
Parikh, K, Cang, S, Sekhri, A and Liu, D (2014) Selective inhibitors of nuclear export (SINE)–a novel class of anti-cancer agents. Journal of Hematology & Oncology 7, 78.Google Scholar
Pemberton, LF and Paschal, BM (2005) Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic 6(3), 187198.Google Scholar
Peterson, KM, Singh, U and Petri, WA (2011) Enteric amebiasis. In Guerrant, R, Walker, DH and Weller, PF (eds). Tropical Infectious Diseases: Principles, Pathogens and Practice. Philadelphia, Saunders Elsevier, p. 614.Google Scholar
Plattner, H and Verkhratsky, A (2015) The ancient roots of calcium signalling evolutionary tree. Cell Calcium 57(3), 123132.Google Scholar
Pritt, BS and Clark, CG (2008) Amebiasis. Mayo Clinic Proceedings 83(10), 11541159; quiz 1159–1160.Google Scholar
Quach, J, St-Pierre, J and Chadee, K (2014) The future for vaccine development against Entamoeba histolytica. Hum Vaccin Immunother 10(6), 15141521.Google Scholar
Ralston, KS (2015) Chew on this: amoebic trogocytosis and host cell killing by Entamoeba histolytica. Trends in Parasitology 31(9), 442452.Google Scholar
Ralston, KS, Solga, MD, Mackey-Lawrence, NM, Somlata, Bhattacharya, A and Petri, WA Jr (2014) Trogocytosis by Entamoeba histolytica contributes to cell killing and tissue invasion. Nature 508(7497), 526530.Google Scholar
Rout, AK, Padhan, N, Barnwal, RP, Bhattacharya, A and Chary, KV (2011) Calmodulin-like protein from Entamoeba histolytica: solution structure and calcium-binding properties of a partially folded protein. Biochemistry 50(2), 181193.Google Scholar
Rout, MP and Aitchison, JD (2001) The nuclear pore complex as a transport machine. Journal of Biological Chemistry 276(20), 1659316596.Google Scholar
Rout, MP and Field, MC (2001) Isolation and characterization of subnuclear compartments from Trypanosoma brucei. Identification of a major repetitive nuclear lamina component. Journal of Biological Chemistry 276(41), 3826138271.Google Scholar
Sahoo, N, Labruyere, E, Bhattacharya, S, Sen, P, Guillen, N and Bhattacharya, A (2004) Calcium binding protein 1 of the protozoan parasite Entamoeba histolytica interacts with actin and is involved in cytoskeleton dynamics. Journal of Cell Science 117(Pt 16), 36253634.Google Scholar
Saito-Nakano, Y, Loftus, BJ, Hall, N and Nozaki, T (2005) The diversity of Rab GTPases in Entamoeba histolytica. Experimental Parasitology 110(3), 244252.Google Scholar
Salit, IE, Khairnar, K, Gough, K and Pillai, DR (2009) A possible cluster of sexually transmitted Entamoeba histolytica: genetic analysis of a highly virulent strain. Clinical Infectious Diseases 49(3), 346353.Google Scholar
Senapedis, WT, Baloglu, E and Landesman, Y (2014) Clinical translation of nuclear export inhibitors in cancer. Seminars in Cancer Biology 27, 7486.Google Scholar
Serpeloni, M, Vidal, NM, Goldenberg, S, Avila, AR and Hoffmann, FG (2011) Comparative genomics of proteins involved in RNA nucleocytoplasmic export. BMC Evolutionary Biology 11, 7.Google Scholar
Shah, SM, Usmanghani, K, Akhtar, N, Akram, M, Asif, HM and Hasan, MM (2016) Clinical study on the efficacy of Amoebex (coded herbal drug) compared with metronidazole for the treatment of amoebic dysentery. Pakistan Journal of Pharmaceutical Sciences 29(6), 20052014.Google Scholar
Shechter, S, Thomas, DR, Lundberg, L, Pinkham, C, Lin, SC, Wagstaff, KM, Debono, A, Kehn-Hall, K and Jans, DA (2017) Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using in silico structure-based-drug-design. Scientific Reports 7(1), 17705.Google Scholar
Singh, RS, Walia, AK and Kanwar, JR (2016) Protozoa lectins and their role in host-pathogen interactions. Biotechnology Advances 34(5), 10181029.Google Scholar
Somlata, , Bhattacharya, S and Bhattacharya, A (2011) A C2 domain protein kinase initiates phagocytosis in the protozoan parasite Entamoeba histolytica. Nature Communications 2, 230.Google Scholar
Somlata, , Kamanna, S, Agrahari, M, Babuta, M, Bhattacharya, S and Bhattacharya, A (2012) Autophosphorylation of Ser428 of EhC2PK plays a critical role in regulating erythrophagocytosis in the parasite Entamoeba histolytica. Journal of Biological Chemistry 287(14), 1084410852.Google Scholar
Stanley, SL Jr. (2003) Amoebiasis. Lancet 361(9362), 10251034.Google Scholar
Uribe, R, Almaraz Barrera Mde, J, Robles-Flores, M, Mendoza Hernandez, G, Gonzalez-Robles, A, Hernandez-Rivas, R, Guillen, N and Vargas, M (2012) A functional study of nucleocytoplasmic transport signals of the EhNCABP166 protein from Entamoeba histolytica. Parasitology 139(13), 16971710.Google Scholar
van Hal, SJ, Stark, DJ, Fotedar, R, Marriott, D, Ellis, JT and Harkness, JL (2007) Amoebiasis: current status in Australia. Medical Journal of Australia 186(8), 412416.Google Scholar
Verma, D, Murmu, A, Gourinath, S, Bhattacharya, A and Chary, KVR (2017) Structure of Ca2+-binding protein-6 from Entamoeba histolytica and its involvement in trophozoite proliferation regulation. PLoS Pathogens 13(5), e1006332.Google Scholar
Verma, K and Datta, S (2017) The monomeric GTPase Rab35 regulates phagocytic cup formation and Phagosomal maturation in Entamoeba histolytica. Journal of Biological Chemistry 292(12), 49604975.Google Scholar
Verma, K, Saito-Nakano, Y, Nozaki, T and Datta, S (2015) Insights into endosomal maturation of human holo-transferrin in the enteric parasite Entamoeba histolytica: essential roles of Rab7A and Rab5 in biogenesis of giant early endocytic vacuoles. Cellular Microbiology 17(12), 17791796.Google Scholar
Verma, K, Nozaki, T and Datta, S (2016) Role of EhRab7A in phagocytosis of type 1 fimbriated E. coli by Entamoeba histolytica. Molecular Microbiology 102(6), 10431061.Google Scholar
Wagstaff, KM and Jans, DA (2009) Importins and beyond: non-conventional nuclear transport mechanisms. Traffic 10(9), 11881198.Google Scholar
Wang, C, Yang, SNY, Smith, K, Forwood, JK and Jans, DA (2017) Nuclear import inhibitor N-(4-hydroxyphenyl) retinamide targets Zika virus (ZIKV) nonstructural protein 5 to inhibit ZIKV infection. Biochemical and Biophysical Research Communications 493(4), 15551559.Google Scholar
Wente, SR and Rout, MP (2010) The nuclear pore complex and nuclear transport. Cold Spring Harbor Perspectives in Biology 2(10), a000562.Google Scholar
Yimer, M, Zenebe, Y, Mulu, W, Abera, B and Saugar, JM (2017) Molecular prevalence of Entamoeba histolytica/dispar infection among patients attending four health centres in north-west Ethiopia. Tropical Doctor 47(1), 1115.Google Scholar