Dual stage synthesis and crucial role of cytoadherence-linked asexual gene 9 in the surface expression of malaria parasite var proteins

Suchi Goel, Manojkumar Valiyaveettil, Rajeshwara N. Achur, Atul Goyal, Denise Mattei, Ali Salanti, Katharine R. Trenholme, Donald L. Gardiner, D. Channe Gowda

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Abstract

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate the adherence of parasite-infected red blood cells (IRBCs) to various host receptors. A previous study has shown that the parasite protein, cytoadherence-linked asexual gene 9 (CLAG9), is also essential for IRBC adherence. However, how CLAG9 influences this process remains unknown. In this study, we show that CLAG9 interacts with VAR2CSA, a PfEMP1 that mediates IRBC adherence to chondroitin 4-sulfate in the placenta. Importantly, our results show that the adherent parasites synthesize CLAG9 at two stages - the early ring and late trophozoite stages. Localization studies revealed that a substantial level of CLAG9 is located mainly at or in close proximity of the IRBC membrane in association with VAR2CSA. Upon treatment of IRBCs with trypsin, a significant amount of CLAG9 (≈150 kDa) was converted into ≈142-kDa polypeptide. Together these data demonstrate that a considerable amount of CLAG9 is embedded in the IRBC membrane such that at least a portion of the polypeptide at either N or C terminus is exposed on the cell surface. In parasites lacking CLAG9, VAR2CSA failed to express on the IRBC surface andwas located within the parasite. Based on these findings, we propose that CLAG9 plays a critical role in the trafficking of PfEMP1s onto the IRBC surface. These results have important implications for the development of therapeutics for cerebral, placental, and other cytoadherence-associated malaria illnesses.

Original languageEnglish (US)
Pages (from-to)16643-16648
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number38
DOIs
StatePublished - Sep 21 2010

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Malaria
Parasites
Erythrocytes
Genes
Proteins
Cell Membrane
Trophozoites
Peptides
Chondroitin Sulfates
Trypsin
Placenta

All Science Journal Classification (ASJC) codes

  • General

Cite this

Goel, Suchi ; Valiyaveettil, Manojkumar ; Achur, Rajeshwara N. ; Goyal, Atul ; Mattei, Denise ; Salanti, Ali ; Trenholme, Katharine R. ; Gardiner, Donald L. ; Gowda, D. Channe. / Dual stage synthesis and crucial role of cytoadherence-linked asexual gene 9 in the surface expression of malaria parasite var proteins. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 38. pp. 16643-16648.
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Dual stage synthesis and crucial role of cytoadherence-linked asexual gene 9 in the surface expression of malaria parasite var proteins. / Goel, Suchi; Valiyaveettil, Manojkumar; Achur, Rajeshwara N.; Goyal, Atul; Mattei, Denise; Salanti, Ali; Trenholme, Katharine R.; Gardiner, Donald L.; Gowda, D. Channe.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 38, 21.09.2010, p. 16643-16648.

Research output: Contribution to journalArticle

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AU - Goel, Suchi

AU - Valiyaveettil, Manojkumar

AU - Achur, Rajeshwara N.

AU - Goyal, Atul

AU - Mattei, Denise

AU - Salanti, Ali

AU - Trenholme, Katharine R.

AU - Gardiner, Donald L.

AU - Gowda, D. Channe

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AB - Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate the adherence of parasite-infected red blood cells (IRBCs) to various host receptors. A previous study has shown that the parasite protein, cytoadherence-linked asexual gene 9 (CLAG9), is also essential for IRBC adherence. However, how CLAG9 influences this process remains unknown. In this study, we show that CLAG9 interacts with VAR2CSA, a PfEMP1 that mediates IRBC adherence to chondroitin 4-sulfate in the placenta. Importantly, our results show that the adherent parasites synthesize CLAG9 at two stages - the early ring and late trophozoite stages. Localization studies revealed that a substantial level of CLAG9 is located mainly at or in close proximity of the IRBC membrane in association with VAR2CSA. Upon treatment of IRBCs with trypsin, a significant amount of CLAG9 (≈150 kDa) was converted into ≈142-kDa polypeptide. Together these data demonstrate that a considerable amount of CLAG9 is embedded in the IRBC membrane such that at least a portion of the polypeptide at either N or C terminus is exposed on the cell surface. In parasites lacking CLAG9, VAR2CSA failed to express on the IRBC surface andwas located within the parasite. Based on these findings, we propose that CLAG9 plays a critical role in the trafficking of PfEMP1s onto the IRBC surface. These results have important implications for the development of therapeutics for cerebral, placental, and other cytoadherence-associated malaria illnesses.

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