Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites

ABSTRACT Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signaling pathways. Exposure of P. falciparum merozoites to the physiological signal of low K+, as found in blood plasma, leads to a rise in cytosolic Ca2+, which mediates microneme secretio...

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Autores principales:	Kunal R. More, Inderjeet Kaur, Quentin Giai Gianetto, Brandon M. Invergo, Thibault Chaze, Ravi Jain, Christéle Huon, Petra Gutenbrunner, Hendrik Weisser, Mariette Matondo, Jyoti S. Choudhary, Gordon Langsley, Shailja Singh, Chetan E. Chitnis
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	host cell invasion host-parasite interaction malaria signaling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cf8e5574eaf442db8acf7c08a6cec1bf
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spelling	oai:doaj.org-article:cf8e5574eaf442db8acf7c08a6cec1bf2021-11-15T15:56:43ZPhosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites10.1128/mBio.01287-202150-7511https://doaj.org/article/cf8e5574eaf442db8acf7c08a6cec1bf2020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01287-20https://doaj.org/toc/2150-7511ABSTRACT Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signaling pathways. Exposure of P. falciparum merozoites to the physiological signal of low K+, as found in blood plasma, leads to a rise in cytosolic Ca2+, which mediates microneme secretion, motility, and invasion. We have used global phosphoproteomic analysis of merozoites to identify signaling pathways that are activated during invasion. Using quantitative phosphoproteomics, we found 394 protein phosphorylation site changes in merozoites subjected to different ionic environments (high K+/low K+), 143 of which were Ca2+ dependent. These included a number of signaling proteins such as catalytic and regulatory subunits of protein kinase A (PfPKAc and PfPKAr) and calcium-dependent protein kinase 1 (PfCDPK1). Proteins of the 14-3-3 family interact with phosphorylated target proteins to assemble signaling complexes. Here, using coimmunoprecipitation and gel filtration chromatography, we demonstrate that Pf14-3-3I binds phosphorylated PfPKAr and PfCDPK1 to mediate the assembly of a multiprotein complex in P. falciparum merozoites. A phospho-peptide, P1, based on the Ca2+-dependent phosphosites of PKAr, binds Pf14-3-3I and disrupts assembly of the Pf14-3-3I-mediated multiprotein complex. Disruption of the multiprotein complex with P1 inhibits microneme secretion and RBC invasion. This study thus identifies a novel signaling complex that plays a key role in merozoite invasion of RBCs. Disruption of this signaling complex could serve as a novel approach to inhibit blood-stage growth of malaria parasites. IMPORTANCE Invasion of red blood cells (RBCs) by Plasmodium falciparum merozoites is a complex process that is regulated by intricate signaling pathways. Here, we used phosphoproteomic profiling to identify the key proteins involved in signaling events during invasion. We found changes in the phosphorylation of various merozoite proteins, including multiple kinases previously implicated in the process of invasion. We also found that a phosphorylation-dependent multiprotein complex including signaling kinases assembles during the process of invasion. Disruption of this multiprotein complex impairs merozoite invasion of RBCs, providing a novel approach for the development of inhibitors to block the growth of blood-stage malaria parasites.Kunal R. MoreInderjeet KaurQuentin Giai GianettoBrandon M. InvergoThibault ChazeRavi JainChristéle HuonPetra GutenbrunnerHendrik WeisserMariette MatondoJyoti S. ChoudharyGordon LangsleyShailja SinghChetan E. ChitnisAmerican Society for Microbiologyarticlehost cell invasionhost-parasite interactionmalariasignalingMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	host cell invasion host-parasite interaction malaria signaling Microbiology QR1-502
spellingShingle	host cell invasion host-parasite interaction malaria signaling Microbiology QR1-502 Kunal R. More Inderjeet Kaur Quentin Giai Gianetto Brandon M. Invergo Thibault Chaze Ravi Jain Christéle Huon Petra Gutenbrunner Hendrik Weisser Mariette Matondo Jyoti S. Choudhary Gordon Langsley Shailja Singh Chetan E. Chitnis Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites
description	ABSTRACT Red blood cell (RBC) invasion by Plasmodium merozoites requires multiple steps that are regulated by signaling pathways. Exposure of P. falciparum merozoites to the physiological signal of low K+, as found in blood plasma, leads to a rise in cytosolic Ca2+, which mediates microneme secretion, motility, and invasion. We have used global phosphoproteomic analysis of merozoites to identify signaling pathways that are activated during invasion. Using quantitative phosphoproteomics, we found 394 protein phosphorylation site changes in merozoites subjected to different ionic environments (high K+/low K+), 143 of which were Ca2+ dependent. These included a number of signaling proteins such as catalytic and regulatory subunits of protein kinase A (PfPKAc and PfPKAr) and calcium-dependent protein kinase 1 (PfCDPK1). Proteins of the 14-3-3 family interact with phosphorylated target proteins to assemble signaling complexes. Here, using coimmunoprecipitation and gel filtration chromatography, we demonstrate that Pf14-3-3I binds phosphorylated PfPKAr and PfCDPK1 to mediate the assembly of a multiprotein complex in P. falciparum merozoites. A phospho-peptide, P1, based on the Ca2+-dependent phosphosites of PKAr, binds Pf14-3-3I and disrupts assembly of the Pf14-3-3I-mediated multiprotein complex. Disruption of the multiprotein complex with P1 inhibits microneme secretion and RBC invasion. This study thus identifies a novel signaling complex that plays a key role in merozoite invasion of RBCs. Disruption of this signaling complex could serve as a novel approach to inhibit blood-stage growth of malaria parasites. IMPORTANCE Invasion of red blood cells (RBCs) by Plasmodium falciparum merozoites is a complex process that is regulated by intricate signaling pathways. Here, we used phosphoproteomic profiling to identify the key proteins involved in signaling events during invasion. We found changes in the phosphorylation of various merozoite proteins, including multiple kinases previously implicated in the process of invasion. We also found that a phosphorylation-dependent multiprotein complex including signaling kinases assembles during the process of invasion. Disruption of this multiprotein complex impairs merozoite invasion of RBCs, providing a novel approach for the development of inhibitors to block the growth of blood-stage malaria parasites.
format	article
author	Kunal R. More Inderjeet Kaur Quentin Giai Gianetto Brandon M. Invergo Thibault Chaze Ravi Jain Christéle Huon Petra Gutenbrunner Hendrik Weisser Mariette Matondo Jyoti S. Choudhary Gordon Langsley Shailja Singh Chetan E. Chitnis
author_facet	Kunal R. More Inderjeet Kaur Quentin Giai Gianetto Brandon M. Invergo Thibault Chaze Ravi Jain Christéle Huon Petra Gutenbrunner Hendrik Weisser Mariette Matondo Jyoti S. Choudhary Gordon Langsley Shailja Singh Chetan E. Chitnis
author_sort	Kunal R. More
title	Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites
title_short	Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites
title_full	Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites
title_fullStr	Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites
title_full_unstemmed	Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites
title_sort	phosphorylation-dependent assembly of a 14-3-3 mediated signaling complex during red blood cell invasion by <named-content content-type="genus-species">plasmodium falciparum</named-content> merozoites
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/cf8e5574eaf442db8acf7c08a6cec1bf
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Phosphorylation-Dependent Assembly of a 14-3-3 Mediated Signaling Complex during Red Blood Cell Invasion by <named-content content-type="genus-species">Plasmodium falciparum</named-content> Merozoites

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