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Strain-specific disruption of interferon-stimulated N-myc and STAT interactor (NMI) function by Toxoplasma gondii type I ROP18 in human cells

Published online by Cambridge University Press:  30 July 2020

Jing Xia ,
Matthew L. Blank ,
Li-Juan Zhou ,
Shui-Zhen Wu ,
Hong-Juan Peng  and
Jon P. Boyle Open the ORCID record for Jon P. Boyle [Opens in a new window]
Jing Xia
Affiliation:
Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province510515, P.R. China Department of Biological Sciences, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania15260, USA
Matthew L. Blank
Affiliation:
Department of Biological Sciences, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania15260, USA
Li-Juan Zhou
Affiliation:
Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province510515, P.R. China
Shui-Zhen Wu
Affiliation:
Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province510515, P.R. China
Hong-Juan Peng*
Affiliation:
Department of Pathogen Biology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province510515, P.R. China
Jon P. Boyle*
Affiliation:
Department of Biological Sciences, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania15260, USA
*
Author for correspondence: Hong-Juan Peng, hongjuan@smu.edu.cn, and Jon P. Boyle, E-mail: boylej@pitt.edu
Author for correspondence: Hong-Juan Peng, hongjuan@smu.edu.cn, and Jon P. Boyle, E-mail: boylej@pitt.edu
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Abstract

Toxoplasma gondii rhoptry protein TgROP18 is a polymorphic virulence effector that targets immunity-related GTPases (IRGs) in rodents. Given that IRGs are uniquely diversified in rodents and not in other T. gondii intermediate hosts, the role of TgROP18 in manipulating non-rodent cells is unclear. Here we show that in human cells TgROP18I interacts with the interferon-gamma-inducible protein N-myc and STAT interactor (NMI) and that this is a property that is unique to the type I TgROP18 allele. Specifically, when expressed ectopically in mammalian cells only TgROP18I co-immunoprecipitates with NMI in IFN-γ-treated cells, while TgROP18II does not. In parasites expressing TgROP18I or TgROP18II, NMI only co-immunoprecipitates with TgROP18I and this is associated with allele-specific immunolocalization of NMI on the parasitophorous vacuolar membrane (PVM). We also found that TgROP18I reduces NMI association with IFN-γ-activated sequences (GAS) in the IRF1 gene promoter. Finally, we determined that polymorphisms in the C-terminal kinase domain of TgROP18I are required for allele-specific effects on NMI. Together, these data further define new host pathway targeted by TgROP18I and provide the first function driven by allelic differences in the highly polymorphic ROP18 locus.

Keywords

Diversifying selectionNMIROP18Toxoplasma gondii
Type
Research Article
Information
Parasitology , Volume 147 , Issue 13 , November 2020 , pp. 1433 - 1442
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Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

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References

Aaronson, DS and Horvath, CM (2002) A road map for those who don't know JAK-STAT. Science (New York. N.Y) 296, 1653–1655.CrossRefGoogle ScholarPubMed
Ahuja, D, Saenz-Robles, MT and Pipas, JM (2005) SV40 Large T antigen targets multiple cellular pathways to elicit cellular transformation. Oncogene 24, 7729–7745.Google ScholarPubMed
Barragan, A and Sibley, LD (2002) Transepithelial migration of Toxoplasma Gondii is linked to parasite motility and virulence. The Journal of Experimental Medicine 195, 1625–1633.CrossRefGoogle ScholarPubMed
Behnke, MS, Fentress, SJ, Mashayekhi, M, Li, LX, Taylor, GA and Sibley, LD (2012) The polymorphic pseudokinase ROP5 controls virulence in Toxoplasma Gondii by regulating the active kinase ROP18. PLoS Pathogens 8, e1002992.CrossRefGoogle ScholarPubMed
Bekpen, C, Hunn, JP, Rohde, C, Parvanova, I, Guethlein, L, Dunn, DM, Glowalla, E, Leptin, M and Howard, JC (2005) The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biology 6, R92.CrossRefGoogle ScholarPubMed
Boothroyd, JC and Dubremetz, JF (2008) Kiss and spit: the dual roles of Toxoplasma rhoptries. Nature Reviews. Microbiology 6, 79–88.10.1038/nrmicro1800CrossRefGoogle ScholarPubMed
Boyle, JP, Saeij, JP and Boothroyd, JC (2007) Toxoplasma Gondii: inconsistent dissemination patterns following oral infection in mice. Experimental Parasitology 116, 302–305.CrossRefGoogle ScholarPubMed
Budenholzer, L, Cheng, CL, Li, Y and Hochstrasser, M (2017) Proteasome structure and assembly. Journal of Molecular Biology 429, 3500–3524.CrossRefGoogle Scholar
Casper, J, Zweig, AS, Villarreal, C, Tyner, C, Speir, ML, Rosenbloom, KR, Raney, BJ, Lee, CM, Lee, BT, Karolchik, D, Hinrichs, AS, Haeussler, M, Guruvadoo, L, Navarro Gonzalez, J, Gibson, D, Fiddes, IT, Eisenhart, C, Diekhans, M, Clawson, H, Barber, GP, Armstrong, J, Haussler, D, Kuhn, RM and Kent, WJ (2018) The UCSC genome browser database: 2018 update. Nucleic Acids Research 46, D762–d769.CrossRefGoogle ScholarPubMed
Du, J, An, R, Chen, L, Shen, Y, Chen, Y, Cheng, L, Jiang, Z, Zhang, A, Yu, L, Chu, D, Shen, Y, Luo, Q, Chen, H, Wan, L, Li, M, Xu, X and Shen, J (2014) Toxoplasma Gondii virulence factor ROP18 inhibits the host NF-kappaB pathway by promoting p65 degradation. The Journal of Biological Chemistry 289, 12578–12592.CrossRefGoogle ScholarPubMed
El Hajj, H, Lebrun, M, Arold, ST, Vial, H, Labesse, G and and Dubremetz, JF (2007) ROP18 Is a rhoptry kinase controlling the intracellular proliferation of Toxoplasma gondii. PLoS Pathogens 3, e14.CrossRefGoogle ScholarPubMed
Feng, L, Sheng, J, Vu, GP, Liu, Y, Foo, C, Wu, S, Trang, P, Paliza-Carre, M, Ran, Y, Yang, X, Sun, X, Deng, Z, Zhou, T, Lu, S, Li, H and Liu, F (2018) Human cytomegalovirus UL23 inhibits transcription of interferon-gamma stimulated genes and blocks antiviral interferon-gamma responses by interacting with human N-myc interactor protein. PLoS Pathogens 14, e1006867.CrossRefGoogle ScholarPubMed
Fentress, SJ, Behnke, MS, Dunay, IR, Mashayekhi, M, Rommereim, LM, Fox, BA, Bzik, DJ, Taylor, GA, Turk, BE, Lichti, CF, Townsend, RR, Qiu, W, Hui, R, Beatty, WL and Sibley, LD (2010) Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence. Cell Host & Microbe 8, 484–495.CrossRefGoogle ScholarPubMed
Fentress, SJ, Steinfeldt, T, Howard, JC and Sibley, LD (2012) The arginine-rich N-terminal domain of ROP18 is necessary for vacuole targeting and virulence of Toxoplasma gondii. Cellular Microbiology 14, 1921–1933.CrossRefGoogle ScholarPubMed
Gay, G, Braun, L, Brenier-Pinchart, MP, Vollaire, J, Josserand, V, Bertini, RL, Varesano, A, Touquet, B, De Bock, PJ, Coute, Y, Tardieux, I, Bougdour, A and Hakimi, MA (2016) Toxoplasma Gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-gamma-mediated host defenses. The Journal of Experimental Medicine 213, 1779–1798.CrossRefGoogle ScholarPubMed
Gibson, DG, Young, L, Chuang, RY, Venter, JC, Hutchison, CA 3rd and Smith, HO (2009) Enzymatic assembly of DNA molecules up to several hundred kilobases. Nature Methods 6, 343–345.CrossRefGoogle ScholarPubMed
Hu, X, Yang, W, Liu, R, Geng, Y, Qiao, W and Tan, J (2014) N-Myc interactor inhibits prototype foamy virus by sequestering viral Tas protein in the cytoplasm. Journal of Virology 88, 7036–7044.10.1128/JVI.00799-14CrossRefGoogle ScholarPubMed
Huber, LA and Teis, D (2016) Lysosomal signaling in control of degradation pathways. Current Opinion in Cell Biology 39, 8–14.CrossRefGoogle ScholarPubMed
Hunter, CA and Sibley, LD (2012) Modulation of innate immunity by Toxoplasma Gondii virulence effectors. Nature Reviews. Microbiology 10, 766–778.CrossRefGoogle ScholarPubMed
Liu, J, Huang, Y, Huang, X, Li, C, Ni, SW, Yu, Y and Qin, Q (2019) Grouper DDX41 exerts antiviral activity against fish iridovirus and nodavirus infection. Fish & Shellfish Immunology 91, 40–49.CrossRefGoogle ScholarPubMed
Mordue, DG, Monroy, F, La Regina, M, Dinarello, CA and Sibley, LD (2001) Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. Journal of Immunology (Baltimore, Md: 1950) 167, 4574–4584.CrossRefGoogle ScholarPubMed
Morrison, DA (2009) Evolution of the Apicomplexa: where are we now? Trends in Parasitology 25, 375–382.CrossRefGoogle ScholarPubMed
Murillo-Leon, M, Muller, UB, Zimmermann, I, Singh, S, Widdershooven, P, Campos, C, Alvarez, C, Konen-Waisman, S, Lukes, N, Ruzsics, Z, Howard, JC, Schwemmle, M and Steinfeldt, T (2019) Molecular mechanism for the control of virulent Toxoplasma Gondii infections in wild-derived mice. Nature Communications 10, 1233.CrossRefGoogle ScholarPubMed
Olias, P, Etheridge, RD, Zhang, Y, Holtzman, MJ and Sibley, LD (2016) Toxoplasma effector recruits the Mi-2/NuRD complex to repress STAT1 transcription and block IFN-gamma-dependent gene expression. Cell Host & Microbe 20, 72–82.CrossRefGoogle ScholarPubMed
Perera, NCN, Godahewa, GI, Nam, B-H and Lee, J (2016) Molecular structure and immune-stimulated transcriptional modulation of the first teleostean IFP35 counterpart from rockfish (Sebastes schlegelii). Fish & Shellfish Immunology 56, 496–505.CrossRefGoogle Scholar
Platanias, LC (2005) Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature Reviews. Immunology 5, 375–386.CrossRefGoogle ScholarPubMed
Qiu, W, Wernimont, A, Tang, K, Taylor, S, Lunin, V, Schapira, M, Fentress, S, Hui, R and Sibley, LD (2009) Novel structural and regulatory features of rhoptry secretory kinases in Toxoplasma gondii. The EMBO Journal 28, 969–979.CrossRefGoogle ScholarPubMed
Radke, JR, Striepen, B, Guerini, MN, Jerome, ME, Roos, DS and White, MW (2001) Defining the cell cycle for the tachyzoite stage of Toxoplasma gondii. Molecular and Biochemical Parasitology 115, 165–175.CrossRefGoogle ScholarPubMed
Rauch, I, Muller, M and Decker, T (2013) The regulation of inflammation by interferons and their STATs. Jak-stat 2, e23820.CrossRefGoogle Scholar
Reese, ML and Boothroyd, JC (2009) A helical membrane-binding domain targets the Toxoplasma ROP2 family to the parasitophorous vacuole. Traffic (Copenhagen, Denmark) 10, 1458–1470.CrossRefGoogle ScholarPubMed
Reese, ML and Boothroyd, JC (2011) A conserved non-canonical motif in the pseudoactive site of the ROP5 pseudokinase domain mediates its effect on Toxoplasma virulence. The Journal of Biological Chemistry 33, 29366–29375.CrossRefGoogle Scholar
Reese, ML, Zeiner, GM, Saeij, JP, Boothroyd, JC and Boyle, JP (2011) Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence. Proceedings of the National Academy of Sciences of the United States of America 108, 9625–9630.CrossRefGoogle ScholarPubMed
Saadatnia, G and Golkar, M (2012) A review on human toxoplasmosis. Scandinavian Journal of Infectious Diseases 44, 805–814.CrossRefGoogle ScholarPubMed
Sadak, A, Taghy, Z, Fortier, B and Dubremetz, JF (1988) Characterization of a family of rhoptry proteins of Toxoplasma gondii. Molecular and Biochemical Parasitology 29, 203–211.10.1016/0166-6851(88)90075-8CrossRefGoogle ScholarPubMed
Saeij, JP, Boyle, JP, Coller, S, Taylor, S, Sibley, LD, Brooke-Powell, ET, Ajioka, JW and Boothroyd, JC (2006) Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science (New York, N.Y.) 314, 1780–1783.CrossRefGoogle ScholarPubMed
Schneider, CA, Rasband, WS and Eliceiri, KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nature Methods 9, 671–675.CrossRefGoogle ScholarPubMed
Sibley, LD and Ajioka, JW (2008) Population structure of Toxoplasma Gondii: clonal expansion driven by infrequent recombination and selective sweeps. Annual Review of Microbiology 62, 329–351.CrossRefGoogle ScholarPubMed
Sibley, LD and Boothroyd, JC (1992) Virulent strains of Toxoplasma Gondii comprise a single clonal lineage. Nature 359, 82–85.CrossRefGoogle ScholarPubMed
Stark, GR (2007) How cells respond to interferons revisited: from early history to current complexity. Cytokine & Growth Factor Reviews 18, 419–423.CrossRefGoogle ScholarPubMed
Steinfeldt, T, Konen-Waisman, S, Tong, L, Pawlowski, N, Lamkemeyer, T, Sibley, LD, Hunn, JP and Howard, JC (2010) Phosphorylation of mouse immunity-related GTPase (IRG) resistance proteins is an evasion strategy for virulent Toxoplasma gondii. PLoS Biology 8, e1000576.CrossRefGoogle ScholarPubMed
Suzuki, Y, Orellana, MA, Schreiber, RD and Remington, JS (1988) Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science (New York, N.Y.) 240, 516–518.CrossRefGoogle ScholarPubMed
Tamura, K, Stecher, G, Peterson, D, Filipski, A and Kumar, S (2013) MEGA6: molecular evolutionary genetics analysis version 6.0. Molecular Biology and Evolution 30, 2725–2729.CrossRefGoogle ScholarPubMed
Taniguchi, T, Ogasawara, K, Takaoka, A and Tanaka, N (2001) IRF Family of transcription factors as regulators of host defense. Annual Review of Immunology 19, 623–655.CrossRefGoogle ScholarPubMed
Taylor, S, Barragan, A, Su, C, Fux, B, Fentress, SJ, Tang, K, Beatty, WL, Hajj, HE, Jerome, M, Behnke, MS, White, M, Wootton, JC and Sibley, LD (2006) A secreted serine-threonine kinase determines virulence in the eukaryotic pathogen Toxoplasma gondii. Science (New York, N.Y.) 314, 1776–1780.CrossRefGoogle ScholarPubMed
Walzer, KA, Adomako-Ankomah, Y, Dam, RA, Herrmann, DC, Schares, G, Dubey, JP and Boyle, JP (2013) Hammondia Hammondi, an avirulent relative of Toxoplasma Gondii, has functional orthologs of known T. gondii Virulence genes. Proceedings of the National Academy of Sciences of the United States of America 110, 7446–7451.CrossRefGoogle Scholar
Wang, J, Wang, Y, Liu, J, Ding, L, Zhang, Q, Li, X, Cao, H, Tang, J and Zheng, SJ (2012) A critical role of N-myc and STAT interactor (Nmi) in foot-and-mouth disease virus (FMDV) 2C-induced apoptosis. Virus Research 170, 59–65.CrossRefGoogle ScholarPubMed
Wang, J, Yang, B, Hu, Y, Zheng, Y, Zhou, H, Wang, Y, Ma, Y, Mao, K, Yang, L, Lin, G, Ji, Y, Wu, X and Sun, B (2013) Negative regulation of Nmi on virus-triggered type I IFN production by targeting IRF7. Journal of immunology (Baltimore, Md.: 1950) 191, 3393–3399.CrossRefGoogle ScholarPubMed
Wu, X, Wang, S, Yu, Y, Zhang, J, Sun, Z, Yan, Y and Zhou, J (2013) Subcellular proteomic analysis of human host cells infected with H3N2 swine influenza virus. Proteomics 13, 3309–3326.CrossRefGoogle ScholarPubMed
Xia, J, Kong, L, Zhou, LJ, Wu, SZ, Yao, LJ, He, C, He, CY and Peng, HJ (2018) Genome-wide bimolecular fluorescence complementation-based proteomic analysis of Toxoplasma gondii ROP18's human interactome shows its key role in regulation of cell immunity and apoptosis. Front Immunol 9, 61.CrossRefGoogle ScholarPubMed
Xu, X, Chai, K, Chen, Y, Lin, Y, Zhang, S, Li, X, Qiao, W and Tan, J (2018) Interferon activates promoter of Nmi gene Via Interferon regulator factor-1. Molecular and Cellular Biochemistry 441, 165–171.CrossRefGoogle ScholarPubMed
Yamamoto, M and Takeda, K (2012) Inhibition of ATF6beta-dependent host adaptive immune response by a Toxoplasma virulence factor ROP18. Virulence 3, 77–80.CrossRefGoogle ScholarPubMed
Yamamoto, M, Ma, JS, Mueller, C, Kamiyama, N, Saiga, H, Kubo, E, Kimura, T, Okamoto, T, Okuyama, M, Kayama, H, Nagamune, K, Takashima, S, Matsuura, Y, Soldati-Favre, D and Takeda, K (2011) ATF6beta Is a host cellular target of the Toxoplasma Gondii virulence factor ROP18. The Journal of Experimental Medicine 208, 1533–1546.CrossRefGoogle ScholarPubMed
Yang, X, Boehm, JS, Yang, X, Salehi-Ashtiani, K, Hao, T, Shen, Y, Lubonja, R, Thomas, SR, Alkan, O, Bhimdi, T, Green, TM, Johannessen, CM, Silver, SJ, Nguyen, C, Murray, RR, Hieronymus, H, Balcha, D, Fan, C, Lin, C, Ghamsari, L, Vidal, M, Hahn, WC, Hill, DE and Root, DE (2011) A public genome-scale lentiviral expression library of human ORFs. Nature Methods 8, 659–661.CrossRefGoogle ScholarPubMed
Yap, GS and Sher, A (1999) Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-gamma- and tumor necrosis factor (TNF)-alpha-dependent host resistance to the intracellular pathogen, Toxoplasma gondii. The Journal of Experimental Medicine 189, 1083–1092.CrossRefGoogle ScholarPubMed
Zhao, Y, Ferguson, DJ, Wilson, DC, Howard, JC, Sibley, LD and Yap, GS (2009) Virulent Toxoplasma Gondii evade immunity-related GTPase-mediated parasite vacuole disruption within primed macrophages. Journal of Immunology (Baltimore, Md.: 1950) 182, 3775–3781.CrossRefGoogle ScholarPubMed
Zhu, M, John, S, Berg, M and Leonard, WJ (1999) Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling. Cell 96, 121–130.CrossRefGoogle ScholarPubMed
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