A unique GCN5 histone acetyltransferase complex controls erythrocyte invasion and virulence in the malaria parasite Plasmodium falciparum.
Acetylation
Chromatin
/ genetics
Erythrocytes
/ metabolism
Gene Expression Regulation
Histone Acetyltransferases
/ genetics
Humans
Hypoxia-Inducible Factor-Proline Dioxygenases
/ genetics
Malaria, Falciparum
/ metabolism
Plasmodium falciparum
/ physiology
Protein Interaction Domains and Motifs
Protozoan Proteins
/ genetics
Virulence
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
28
01
2021
accepted:
21
07
2021
revised:
27
08
2021
pubmed:
18
8
2021
medline:
1
12
2021
entrez:
17
8
2021
Statut:
epublish
Résumé
The histone acetyltransferase GCN5-associated SAGA complex is evolutionarily conserved from yeast to human and functions as a general transcription co-activator in global gene regulation. In this study, we identified a divergent GCN5 complex in Plasmodium falciparum, which contains two plant homeodomain (PHD) proteins (PfPHD1 and PfPHD2) and a plant apetela2 (AP2)-domain transcription factor (PfAP2-LT). To dissect the functions of the PfGCN5 complex, we generated parasite lines with either the bromodomain in PfGCN5 or the PHD domain in PfPHD1 deleted. The two deletion mutants closely phenocopied each other, exhibiting significantly reduced merozoite invasion of erythrocytes and elevated sexual conversion. These domain deletions caused dramatic decreases not only in histone H3K9 acetylation but also in H3K4 trimethylation, indicating synergistic crosstalk between the two euchromatin marks. Domain deletion in either PfGCN5 or PfPHD1 profoundly disturbed the global transcription pattern, causing altered expression of more than 60% of the genes. At the schizont stage, these domain deletions were linked to specific down-regulation of merozoite genes involved in erythrocyte invasion, many of which contain the AP2-LT binding motif and are also regulated by AP2-I and BDP1, suggesting targeted recruitment of the PfGCN5 complex to the invasion genes by these specific factors. Conversely, at the ring stage, PfGCN5 or PfPHD1 domain deletions disrupted the mutually exclusive expression pattern of the entire var gene family, which encodes the virulent factor PfEMP1. Correlation analysis between the chromatin state and alteration of gene expression demonstrated that up- and down-regulated genes in these mutants are highly correlated with the silent and active chromatin states in the wild-type parasite, respectively. Collectively, the PfGCN5 complex represents a novel HAT complex with a unique subunit composition including an AP2 transcription factor, which signifies a new paradigm for targeting the co-activator complex to regulate general and parasite-specific cellular processes in this low-branching parasitic protist.
Identifiants
pubmed: 34403450
doi: 10.1371/journal.ppat.1009351
pii: PPATHOGENS-D-21-00221
pmc: PMC8396726
doi:
Substances chimiques
Chromatin
0
Protozoan Proteins
0
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Histone Acetyltransferases
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009351Subventions
Organisme : NIAID NIH HHS
ID : R01 AI128940
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI089672
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Angew Chem Int Ed Engl. 2017 Jan 16;56(3):827-831
pubmed: 27966810
Gene. 2004 Jul 21;336(2):251-61
pubmed: 15246536
Nucleic Acids Res. 2012 Jan;40(Database issue):D169-79
pubmed: 22102575
J Cell Sci. 2020 Jan 9;133(1):
pubmed: 31862795
Nat Commun. 2020 Mar 20;11(1):1503
pubmed: 32198457
Cold Spring Harb Perspect Biol. 2014 Jul 01;6(7):a018762
pubmed: 24984779
Plant Cell. 2003 Mar;15(3):626-38
pubmed: 12615937
Mol Biochem Parasitol. 2011 Mar;176(1):1-7
pubmed: 21126543
Trends Parasitol. 2017 May;33(5):364-377
pubmed: 28065669
Int J Parasitol. 2010 Jan;40(1):109-21
pubmed: 19765590
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Sci Rep. 2016 Feb 09;6:20498
pubmed: 26858037
Cell Host Microbe. 2015 Jun 10;17(6):741-51
pubmed: 26067602
PLoS One. 2016 Oct 12;11(10):e0164272
pubmed: 27732628
EMBO Rep. 2007 Oct;8(10):959-65
pubmed: 17762879
Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):
pubmed: 28320828
BMC Genomics. 2014 May 08;15:347
pubmed: 24885191
Mol Microbiol. 2011 Apr;80(2):391-406
pubmed: 21306446
PLoS Pathog. 2013 Feb;9(2):e1003170
pubmed: 23468622
Science. 2001 Aug 10;293(5532):1074-80
pubmed: 11498575
PLoS Pathog. 2010 Oct 28;6(10):e1001165
pubmed: 21060817
Front Plant Sci. 2015 Oct 14;6:865
pubmed: 26528322
Nucleic Acids Res. 2016 Mar 18;44(5):2110-24
pubmed: 26578577
Mol Cell Biol. 2013 Mar;33(5):999-1015
pubmed: 23263989
Eukaryot Cell. 2004 Apr;3(2):264-76
pubmed: 15075257
PLoS One. 2013;8(1):e53179
pubmed: 23308157
Trends Biochem Sci. 2011 Jul;36(7):364-72
pubmed: 21514168
Genes Dev. 1997 Jul 1;11(13):1640-50
pubmed: 9224714
Cell. 2005 Apr 8;121(1):25-36
pubmed: 15820676
Cell Host Microbe. 2017 Jun 14;21(6):731-741.e10
pubmed: 28618269
Nature. 2000 Oct 26;407(6807):1018-22
pubmed: 11069183
Biochim Biophys Acta. 2006 Jan-Feb;1759(1-2):69-79
pubmed: 16603259
Cell Host Microbe. 2014 Aug 13;16(2):165-176
pubmed: 25121746
PLoS Pathog. 2010 Feb 26;6(2):e1000784
pubmed: 20195509
Science. 2003 Sep 12;301(5639):1503-8
pubmed: 12893887
Cell Host Microbe. 2018 Apr 11;23(4):557-569.e9
pubmed: 29649445
Mol Cell. 2017 Oct 5;68(1):130-143.e5
pubmed: 28918903
Int J Parasitol. 2017 Jun;47(7):399-407
pubmed: 28414071
Eukaryot Cell. 2008 Jul;7(7):1200-10
pubmed: 18487348
Adv Genet. 2010;70:101-41
pubmed: 20920747
PLoS Pathog. 2014 Jan;10(1):e1003830
pubmed: 24391497
EMBO J. 2017 Sep 15;36(18):2710-2725
pubmed: 28724529
PLoS Pathog. 2010 Feb 05;6(2):e1000746
pubmed: 20140184
Science. 2005 Jan 7;307(5706):82-6
pubmed: 15637271
Nucleic Acids Res. 2007;35(19):6648-62
pubmed: 17913746
Mol Microbiol. 2013 Aug;89(4):660-75
pubmed: 23796209
Curr Opin Microbiol. 2014 Aug;20:153-61
pubmed: 25022240
Nature. 2014 Mar 13;507(7491):248-52
pubmed: 24572369
Cell. 2010 Sep 17;142(6):967-80
pubmed: 20850016
Cell Host Microbe. 2018 Mar 14;23(3):407-420.e8
pubmed: 29503181
J Proteomics. 2014 Apr 4;100:37-43
pubmed: 24513533
Annu Rev Microbiol. 2017 Sep 8;71:625-641
pubmed: 28697665
BMC Genomics. 2005 Jul 23;6:100
pubmed: 16042788
Eukaryot Cell. 2007 Apr;6(4):584-91
pubmed: 17307963
Nat Commun. 2018 May 15;9(1):1910
pubmed: 29765020
Essays Biochem. 2010 Sep 20;48(1):45-61
pubmed: 20822485
PLoS Biol. 2009 Apr 14;7(4):e84
pubmed: 19402747
Genome Res. 2004 Aug;14(8):1548-54
pubmed: 15256513
Biol Chem. 2006 Oct-Nov;387(10-11):1469-78
pubmed: 17081121
J Cell Sci. 2010 Apr 1;123(Pt 7):1039-49
pubmed: 20197405
Genome Res. 2014 Jun;24(6):974-88
pubmed: 24671853
Mol Cell. 2002 Nov;10(5):1107-17
pubmed: 12453418
Cell Res. 2011 Mar;21(3):381-95
pubmed: 21321607
Eukaryot Cell. 2007 Jul;6(7):1219-27
pubmed: 17449656
Nature. 2013 Jul 11;499(7457):223-7
pubmed: 23823717
J Biol Chem. 2014 Apr 4;289(14):10069-83
pubmed: 24554700
Mol Microbiol. 2010 Nov;78(4):883-902
pubmed: 20807207
J Biol Chem. 2007 Feb 16;282(7):4408-4416
pubmed: 17166833
J Cell Biol. 2012 Sep 17;198(6):961-71
pubmed: 22986493
Genes Dev. 2012 Mar 15;26(6):527-41
pubmed: 22426530
Int J Parasitol. 2008 Aug;38(10):1083-97
pubmed: 18299133
Nucleic Acids Res. 2005 Jul 21;33(13):3994-4006
pubmed: 16040597
Exp Parasitol. 2010 Oct;126(2):198-202
pubmed: 20435038
Genes Dev. 2014 Sep 15;28(18):1999-2012
pubmed: 25228644
Genome Biol. 2010;11(10):R106
pubmed: 20979621
Genome Res. 2010 Feb;20(2):228-38
pubmed: 20054063
Nat Genet. 2003 Jul;34(3):267-73
pubmed: 12808457
Biochem J. 2009 Jun 12;421(1):107-18
pubmed: 19344311
Nat Protoc. 2011 Feb;6(2):140-6
pubmed: 21293455
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nature. 2005 Nov 3;438(7064):103-7
pubmed: 16267556
Curr Opin Microbiol. 2014 Aug;20:88-95
pubmed: 24945736
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Cell. 2002 Nov 1;111(3):369-79
pubmed: 12419247
Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):255-260
pubmed: 30584102
Nucleic Acids Res. 2009 May;37(8):2596-606
pubmed: 19270070
Cell. 2010 Sep 3;142(5):682-5
pubmed: 20813257
Mol Microbiol. 2007 Dec;66(6):1296-305
pubmed: 18028313
BMC Genomics. 2010 Jan 15;11:34
pubmed: 20078850
Infect Genet Evol. 2011 Jun;11(4):716-24
pubmed: 20708104
Science. 2018 May 4;360(6388):
pubmed: 29724925
Mol Biochem Parasitol. 2004 Sep;137(1):13-21
pubmed: 15279947
Cell Host Microbe. 2014 Aug 13;16(2):177-186
pubmed: 25121747
Nature. 2000 Jan 6;403(6765):41-5
pubmed: 10638745
Trends Biochem Sci. 2017 Nov;42(11):850-861
pubmed: 28964624
Science. 2001 Aug 10;293(5532):1142-6
pubmed: 11498592
Methods. 2001 Dec;25(4):402-8
pubmed: 11846609
PLoS Biol. 2003 Oct;1(1):E5
pubmed: 12929205
Mol Cell. 2007 Jan 12;25(1):31-42
pubmed: 17218269
Nat Methods. 2015 Apr;12(4):357-60
pubmed: 25751142
Nucleic Acids Res. 2001 Feb 1;29(3):850-3
pubmed: 11160909
Eur J Med Chem. 2017 Sep 29;138:26-37
pubmed: 28644986
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):899-902
pubmed: 17209011
Mol Cell. 2004 Feb 27;13(4):573-85
pubmed: 14992726
Eukaryot Cell. 2010 Aug;9(8):1138-49
pubmed: 20453074
Nucleic Acids Res. 2019 Dec 16;47(22):11574-11588
pubmed: 31728527
Mol Cell Proteomics. 2017 Apr;16(4):537-551
pubmed: 28126901
J Biol Chem. 2009 Apr 3;284(14):9411-7
pubmed: 19218239
Curr Opin Cell Biol. 2010 Jun;22(3):374-82
pubmed: 20363118
Mol Biochem Parasitol. 2019 Sep;232:111203
pubmed: 31381949
EMBO J. 2011 Jun 17;30(14):2829-42
pubmed: 21685874
PLoS Pathog. 2010 Dec 16;6(12):e1001223
pubmed: 21187892
J Cell Sci. 2016 Aug 15;129(16):3144-52
pubmed: 27383769
Cell Host Microbe. 2009 Feb 19;5(2):179-90
pubmed: 19218088
Cell. 2005 Apr 8;121(1):13-24
pubmed: 15820675
Gene. 2006 Mar 15;369:53-65
pubmed: 16410041
PLoS Pathog. 2010 Jan 22;6(1):e1000737
pubmed: 20107518
Eukaryot Cell. 2005 Nov;4(11):1942-50
pubmed: 16278461
Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3183-3192
pubmed: 30723152
Biochem J. 2012 Feb 15;442(1):65-75
pubmed: 22081970
Pathogens. 2019 Apr 07;8(2):
pubmed: 30959972
Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5414-9
pubmed: 15797990
Science. 1976 Aug 20;193(4254):673-5
pubmed: 781840
BMC Genomics. 2009 Dec 16;10:610
pubmed: 20015349
PLoS Pathog. 2009 Sep;5(9):e1000569
pubmed: 19730695
Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9655-60
pubmed: 19497874