title: A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria.
abstract: Plasmodium falciparum malaria parasites export the protein PfEMP1 to the surface of infected erythrocytes, enabling them to adhere to receptors in the microvasculature and thereby avoid clearance by the spleen. The gene var2csa encodes the form of PfEMP1 that binds specifically within the placenta, causing pregnancy-associated malaria, and appears to not be expressed in the absence of a placenta. We previously described an upstream open reading frame (uORF) that is responsible for repression of translation of the downstream ORF (dORF) that encodes VAR2CSA, thus keeping the gene silent when parasites infect non-pregnant individuals. To elucidate the molecular mechanism by which this repression is overcome during pregnancy, we stably transformed parasites with reporter gene constructs designed to detect switches in the efficiency of dORF translation. We found that proper regulation of switching relies on two separate components, (i) active translation of the uORF and (ii) sequence-specific characteristics of the surrounding transcript, which together control the ability of the ribosome complex to reinitiate a second round of translation and thus express VAR2CSA. These results provide the first details of a molecular switch that allows parasites take advantage of the unique niche provided by the placenta.
authors: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, 10065, USA.
authors: Cristina
authors: C
authors: Bancells
authors: Kirk W
authors: KW
authors: Deitsch
mesh_terms: D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D016054:DNA, Protozoan / Q000032:analysis; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008288:Malaria; D016778:Malaria, Falciparum / Q000469:parasitology*; D016366:Open Reading Frames; D010920:Placenta / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000235:genetics* / Q000254:growth & development; D011247:Pregnancy
chemical_list: D000953:Antigens, Protozoan; D016054:DNA, Protozoan; C512601:VAR2CSA protein, Plasmodium falciparum
references: Mol Biochem Parasitol. 2011 May;177(1):29-34
references: 21251930
references: Infect Immun. 1999 Oct;67(10):5367-71
references: 10496918
references: Am J Trop Med Hyg. 1984 Jul;33(4):517-25
references: 6383091
references: Nat Struct Mol Biol. 2005 Oct;12(10):835-8
references: 16205706
references: J Infect Dis. 1999 Aug;180(2):464-72
references: 10395863
references: Nature. 2001 Aug 30;412(6850):875-6
references: 11528468
references: Wiley Interdiscip Rev RNA. 2012 Mar-Apr;3(2):195-212
references: 22215521
references: Curr Opin Microbiol. 2006 Aug;9(4):374-80
references: 16814594
references: Nature. 1988 Mar 31;332(6163):457-9
references: 3281025
references: Mol Biochem Parasitol. 2000 Feb 5;105(2):311-5
references: 10693754
references: Mol Cell Biol. 2000 Dec;20(23):8635-42
references: 11073965
references: J Virol. 2011 Jul;85(14):7343-52
references: 21543470
references: Gene. 1999 Jul 8;234(2):187-208
references: 10395892
references: Curr Protein Pept Sci. 2012 Jun;13(4):305-30
references: 22708493
references: Nucleic Acids Res. 2001 Dec 15;29(24):5226-32
references: 11812856
references: J Gen Virol. 2012 Jul;93(Pt 7):1385-1409
references: 22535777
references: Genes Dev. 2007 Dec 1;21(23):3149-62
references: 18056426
references: EMBO J. 2011 Apr 6;30(7):1343-56
references: 21343906
references: Parasitology. 2007;134(Pt 13):1871-6
references: 17958922
references: Cell. 2009 Feb 20;136(4):592-7
references: 19239880
references: Cell. 1995 Jul 14;82(1):101-10
references: 7606775
references: Gene. 2005 Nov 21;361:13-37
references: 16213112
references: FEBS Lett. 2007 Sep 4;581(22):4184-8
references: 17692847
references: Biochem Soc Trans. 2010 Dec;38(6):1558-64
references: 21118126
references: EMBO J. 1998 Sep 15;17(18):5418-26
references: 9736619
references: Nature. 1998 Oct 29;395(6705):851-2
references: 9804416
references: Lancet. 2004 Jan 24;363(9405):283-9
references: 14751701
references: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6
references: 9380737
references: Infect Immun. 2006 Aug;74(8):4875-83
references: 16861676
references: PLoS One. 2008 Apr 23;3(4):e1982
references: 18431472
references: Mol Biol Evol. 2007 Aug;24(8):1744-51
references: 17494029
references: EMBO Rep. 2005 Aug;6(8):775-81
references: 16025132
references: Cell. 2009 Feb 20;136(4):731-45
references: 19239892
references: Mol Biochem Parasitol. 2006 Aug;148(2):169-80
references: 16697476
references: Adv Protein Chem Struct Biol. 2012;86:45-93
references: 22243581
references: Eukaryot Cell. 2011 Apr;10(4):530-9
references: 21317310
references: Nucleic Acids Res. 2001 Feb 1;29(3):850-3
references: 11160909
references: Malar J. 2003 Sep 10;2:27
references: 14565852
references: Annu Rev Microbiol. 2001;55:673-707
references: 11544371
references: Mol Cell Biol. 1987 Oct;7(10):3438-45
references: 3683388
references: Malar J. 2005 Apr 27;4:21
references: 15857512
references: Eur J Biochem. 1996 Mar 15;236(3):747-71
references: 8665893
references: Gene. 2002 Oct 16;299(1-2):1-34
references: 12459250
references: Immunol Lett. 2000 Feb 1;71(2):117-26
references: 10714439
references: PLoS Pathog. 2009 Jan;5(1):e1000256
references: 19119419
references: Acta Trop. 1994 Sep;57(4):239-54
references: 7810381
references: J Exp Med. 2004 Nov 1;200(9):1197-203
references: 15520249
references: J Exp Med. 1984 Nov 1;160(5):1585-90
references: 6208311
references: Am J Trop Med Hyg. 2007 Dec;77(6 Suppl):14-22
references: 18165470
references: Infect Immun. 2013 Feb;81(2):487-95
references: 23208604
references: EMBO J. 1991 Dec;10(12):3887-96
references: 1935908
references: Cell. 1995 Jul 14;82(1):89-100
references: 7606788