TY - JOUR
T1 - Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor
AU - Chan, Sherwin
AU - Frasch, Alejandra
AU - Mandava, Chandra Sekhar
AU - Ch'Ng, Jun Hong
AU - Quintana, Maria Del Pilar
AU - Vesterlund, Mattias
AU - Ghorbal, Mehdi
AU - Joannin, Nicolas
AU - Franzén, Oscar
AU - Lopez-Rubio, Jose Juan
AU - Barbieri, Sonia
AU - Lanzavecchia, Antonio
AU - Sanyal, Suparna
AU - Wahlgren, Mats
N1 - Publisher Copyright:
© 2017 Macmillan Publishers Limited. All rights reserved.
PY - 2017/5/8
Y1 - 2017/5/8
N2 - Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.
AB - Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.
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U2 - 10.1038/nmicrobiol.2017.68
DO - 10.1038/nmicrobiol.2017.68
M3 - Research Article
C2 - 28481333
AN - SCOPUS:85019133411
SN - 2058-5276
VL - 2
JO - Nature Microbiology
JF - Nature Microbiology
M1 - 17068
ER -
