title: Toxoplasma gondii Arginine Methyltransferase 1 (PRMT1) Is Necessary for Centrosome Dynamics during Tachyzoite Cell Division.
abstract: The arginine methyltransferase family (PRMT) has been implicated in a variety of cellular processes, including signal transduction, epigenetic regulation, and DNA repair pathways. PRMT1 is thought to be responsible for the majority of PRMT activity in Toxoplasma gondii, but its exact function is unknown. To further define the biological function of the PRMT family, we generated T. gondii mutants lacking PRMT1 (Δprmt1) by deletion of the PRMT1 gene. Δprmt1 parasites exhibit morphological defects during cell division and grow slowly, and this phenotype reverses in the Δprmt::PRMT1mRFP complemented strain. Tagged PRMT1 localizes primarily in the cytoplasm with enrichment at the pericentriolar material, and the strain lacking PRMT1 is unable to segregate progeny accurately. Unlike wild-type and complemented parasites, Δprmt1 parasites have abnormal daughter buds, perturbed centrosome stoichiometry, and loss of synchronous replication. Whole-genome expression profiling demonstrated differences in expression of cell-cycle-regulated genes in the Δprmt1 strain relative to the complemented Δprmt1::PRMT1mRFP and parental wild-type strains, but these changes do not correlate with a specific block in cell cycle. Although PRMT1's primary biological function was previously proposed to be methylation of histones, our studies suggest that PRMT1 plays an important role within the centrosome to ensure the proper replication of the parasite.
  
  
  OBJECTIVE
  Apicomplexan parasites include several important pathogens, including Toxoplasma gondii, a major cause of opportunistic infections and congenital birth defects. These parasites divide using a unique form of cell division called endodyogeny that is different from those of most eukaryotes. PRMT1 is a conserved arginine methyltransferase that was thought to regulate gene expression of T. gondii by modifying histone methylation. Using genetic techniques, we show that disruption of PRMT1 affects the parasite's ability to perform accurate cell division. Our studies reveal an unexpected role for arginine methylation in centrosome biology and regulation of parasite replication.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Kamal
authors.initials: K
authors.lastname: El Bissati
authors.affiliation: Department of Molecular Medicine, USF Health College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Elena S
authors.initials: ES
authors.lastname: Suvorova
authors.affiliation: Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Molecular Medicine, USF Health College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lucas
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Upadhya
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Laboratory for Macromolecular Analysis and Proteomics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ruth Hogue
authors.initials: RH
authors.lastname: Angeletti
authors.affiliation: Department of Molecular Medicine, USF Health College of Medicine, University of South Florida, Tampa, Florida, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: White
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA louis.weiss@einstein.yu.edu kami.kim@einstein.yu.edu.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA louis.weiss@einstein.yu.edu kami.kim@einstein.yu.edu.
authors.forename: Kami
authors.initials: K
authors.lastname: Kim
mesh_terms: D002455:Cell Division; D018385:Centrosome / Q000378:metabolism*; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005816:Genetic Complementation Test; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D014122:Toxoplasma / Q000166:cytology / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases
references.citation: Mol Biol Cell. 1999 Nov;10(11):3539-47
references.pmid: 10564254
references.citation: Cell Microbiol. 2010 Dec;12(12):1792-808
references.pmid: 20678172
references.citation: Mol Cell Biol. 2000 Jul;20(13):4859-69
references.pmid: 10848611
references.citation: Mol Biochem Parasitol. 2001 Jul;115(2):257-68
references.pmid: 11420112
references.citation: Mol Cell. 2003 Jul;12(1):177-85
references.pmid: 12887903
references.citation: Nature. 2003 Oct 16;425(6959):737-41
references.pmid: 14562106
references.citation: EMBO J. 2004 Jul 7;23(13):2641-50
references.pmid: 15175657
references.citation: J Protozool. 1977 Aug;24(3):449-53
references.pmid: 21288
references.citation: Mol Biochem Parasitol. 2012 Jan;181(1):7-16
references.pmid: 21963440
references.citation: Trends Biochem Sci. 2011 Dec;36(12):633-41
references.pmid: 21975038
references.citation: Cell Microbiol. 2012 Jun;14(6):882-901
references.pmid: 22309152
references.citation: PLoS Biol. 2012;10(12):e1001444
references.pmid: 23239939
references.citation: Mol Cell Proteomics. 2013 Feb;12(2):302-11
references.pmid: 23152538
references.citation: Sci Rep. 2013;3:1311
references.pmid: 23419748
references.citation: J Cell Sci. 2013 Aug 1;126(Pt 15):3344-55
references.pmid: 23729737
references.citation: J Proteomics. 2013 Oct 8;91:210-25
references.pmid: 23872088
references.citation: MBio. 2013;4(6):e00922-13
references.pmid: 24327343
references.citation: Am J Trop Med Hyg. 2014 Jun;90(6):1135-9
references.pmid: 24710615
references.citation: BMC Genomics. 2014;15:515
references.pmid: 24962434
references.citation: PLoS Biol. 2015 Mar;13(3):e1002093
references.pmid: 25734885
references.citation: J Biol Chem. 1998 Jul 3;273(27):16935-45
references.pmid: 9642256
references.citation: Nucleic Acids Res. 2005;33(13):3994-4006
references.pmid: 16040597
references.citation: Mol Biochem Parasitol. 2005 Dec;144(2):206-17
references.pmid: 16198009
references.citation: Mol Cell Biol. 2005 Dec;25(23):10301-14
references.pmid: 16287846
references.citation: J Cell Sci. 2006 Jun 1;119(Pt 11):2236-45
references.pmid: 16684814
references.citation: Mol Biochem Parasitol. 2006 Aug;148(2):109-16
references.pmid: 16644030
references.citation: Eukaryot Cell. 2006 Sep;5(9):1539-49
references.pmid: 16963636
references.citation: Biochim Biophys Acta. 2006 Dec;1764(12):1890-903
references.pmid: 17010682
references.citation: Nat Protoc. 2007;2(6):1445-57
references.pmid: 17545981
references.citation: Eukaryot Cell. 2007 Jun;6(6):889-98
references.pmid: 17468392
references.citation: PLoS Pathog. 2008 Jan;4(1):e10
references.pmid: 18208326
references.citation: Mol Microbiol. 2008 Jun;68(6):1502-18
references.pmid: 18433450
references.citation: BMC Genomics. 2009;10:38
references.pmid: 19159464
references.citation: Nat Cell Biol. 2009 May;11(5):652-8
references.pmid: 19377467
references.citation: Biochem J. 2009 Jul 1;421(1):107-18
references.pmid: 19344311
references.citation: Cell Microbiol. 2009 Oct;11(10):1444-52
references.pmid: 19614666
references.citation: J Proteome Res. 2010 Jan;9(1):359-72
references.pmid: 19886702
references.citation: PLoS Pathog. 2010 Feb;6(2):e1000754
references.pmid: 20140195
references.citation: Cell Microbiol. 2010 Apr 1;12(4):413-23
references.pmid: 20109158
references.citation: PLoS Pathog. 2010 May;6(5):e1000920
references.pmid: 20523899
references.citation: Cell Res. 2010 Sep;20(9):1023-33
references.pmid: 20421892
references.citation: PLoS One. 2010;5(8):e12302
references.pmid: 20808817
references.citation: PLoS Pathog. 2010;6(9):e1001094
references.pmid: 20844581
references.citation: PLoS One. 2010;5(8):e12354
references.pmid: 20865045
references.citation: Curr Biol. 1999 Dec 16-30;9(24):R911-3
references.pmid: 10608922
references.citation: J Biol Chem. 1996 May 24;271(21):12585-94
references.pmid: 8647869
references.citation: Mol Cell Biol. 1996 Jul;16(7):3668-78
references.pmid: 8668183
references.citation: Mol Biochem Parasitol. 1998 Mar 15;91(2):295-305
references.pmid: 9566522
references.citation: Trends Biochem Sci. 1998 Mar;23(3):89-91
references.pmid: 9581497
references.citation: BMC Genomics. 2010;11:603
references.pmid: 20974003
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3767-72
references.pmid: 21321216
references.citation: J Microbiol Methods. 2011 May;85(2):103-13
references.pmid: 21352857
references.citation: Eukaryot Cell. 2011 Aug;10(8):1013-22
references.pmid: 21685318
references.citation: PLoS Pathog. 2011 Sep;7(9):e1002201
references.pmid: 21909263