Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>

ABSTRACT The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant-like P. falciparum calcium-dependent protein kinase 5 (Pf...

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Autores principales:	Sabrina Absalon, Karin Blomqvist, Rachel M. Rudlaff, Travis J. DeLano, Michael P. Pollastri, Jeffrey D. Dvorin
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Plasmodium falciparum calcium-dependent protein kinase egress malaria microneme Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9ff6ac7be22a4dbebd4235997aee08ce
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spelling	oai:doaj.org-article:9ff6ac7be22a4dbebd4235997aee08ce2021-11-15T15:53:26ZCalcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>10.1128/mBio.00130-182150-7511https://doaj.org/article/9ff6ac7be22a4dbebd4235997aee08ce2018-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00130-18https://doaj.org/toc/2150-7511ABSTRACT The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant-like P. falciparum calcium-dependent protein kinase 5 (PfCDPK5). Knockdown of PfCDPK5 results in an egress block where parasites are trapped inside their host cells. The mechanism of this PfCDPK5-dependent block, however, remains unknown. Here, we show that PfCDPK5 colocalizes with a specialized set of parasite organelles known as micronemes and is required for their discharge, implicating failure of this step as the cause of the egress defect in PfCDPK5-deficient parasites. Furthermore, we show that PfCDPK5 cooperates with the P. falciparum cGMP-dependent kinase (PfPKG) to fully activate the protease cascade critical for parasite egress. The PfCDPK5-dependent arrest can be overcome by hyperactivation of PfPKG or by physical disruption of the arrested parasite, and we show that both treatments facilitate the release of the micronemes required for egress. Our results define the molecular mechanism of PfCDPK5 function and elucidate the complex signaling pathway of parasite egress. IMPORTANCE The signs and symptoms of clinical malaria result from the replication of parasites in human blood. Efficient egress of the malaria parasite Plasmodium falciparum out of an infected red blood cell is critical for pathogenesis. The P. falciparum calcium-dependent protein kinase 5 (PfCDPK5) is essential for parasite egress. Following PfCDPK5 knockdown, parasites remain trapped inside their host cell and do not egress, but the mechanism for this block remains unknown. We show that PfCDPK5 colocalizes with parasite organelles known as micronemes. We demonstrate that PfCDPK5 is critical for the discharge of these micronemes and that failure of this step is the molecular mechanism of the parasite egress arrest. We also show that hyperactivation of the cGMP-dependent kinase PKG can overcome this arrest. Our data suggest that small molecules that inhibit the egress signaling pathway could be effective antimalarial therapeutics.Sabrina AbsalonKarin BlomqvistRachel M. RudlaffTravis J. DeLanoMichael P. PollastriJeffrey D. DvorinAmerican Society for MicrobiologyarticlePlasmodium falciparumcalcium-dependent protein kinaseegressmalariamicronemeMicrobiologyQR1-502ENmBio, Vol 9, Iss 1 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium falciparum calcium-dependent protein kinase egress malaria microneme Microbiology QR1-502
spellingShingle	Plasmodium falciparum calcium-dependent protein kinase egress malaria microneme Microbiology QR1-502 Sabrina Absalon Karin Blomqvist Rachel M. Rudlaff Travis J. DeLano Michael P. Pollastri Jeffrey D. Dvorin Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>
description	ABSTRACT The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant-like P. falciparum calcium-dependent protein kinase 5 (PfCDPK5). Knockdown of PfCDPK5 results in an egress block where parasites are trapped inside their host cells. The mechanism of this PfCDPK5-dependent block, however, remains unknown. Here, we show that PfCDPK5 colocalizes with a specialized set of parasite organelles known as micronemes and is required for their discharge, implicating failure of this step as the cause of the egress defect in PfCDPK5-deficient parasites. Furthermore, we show that PfCDPK5 cooperates with the P. falciparum cGMP-dependent kinase (PfPKG) to fully activate the protease cascade critical for parasite egress. The PfCDPK5-dependent arrest can be overcome by hyperactivation of PfPKG or by physical disruption of the arrested parasite, and we show that both treatments facilitate the release of the micronemes required for egress. Our results define the molecular mechanism of PfCDPK5 function and elucidate the complex signaling pathway of parasite egress. IMPORTANCE The signs and symptoms of clinical malaria result from the replication of parasites in human blood. Efficient egress of the malaria parasite Plasmodium falciparum out of an infected red blood cell is critical for pathogenesis. The P. falciparum calcium-dependent protein kinase 5 (PfCDPK5) is essential for parasite egress. Following PfCDPK5 knockdown, parasites remain trapped inside their host cell and do not egress, but the mechanism for this block remains unknown. We show that PfCDPK5 colocalizes with parasite organelles known as micronemes. We demonstrate that PfCDPK5 is critical for the discharge of these micronemes and that failure of this step is the molecular mechanism of the parasite egress arrest. We also show that hyperactivation of the cGMP-dependent kinase PKG can overcome this arrest. Our data suggest that small molecules that inhibit the egress signaling pathway could be effective antimalarial therapeutics.
format	article
author	Sabrina Absalon Karin Blomqvist Rachel M. Rudlaff Travis J. DeLano Michael P. Pollastri Jeffrey D. Dvorin
author_facet	Sabrina Absalon Karin Blomqvist Rachel M. Rudlaff Travis J. DeLano Michael P. Pollastri Jeffrey D. Dvorin
author_sort	Sabrina Absalon
title	Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>
title_short	Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>
title_full	Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>
title_fullStr	Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>
title_full_unstemmed	Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>
title_sort	calcium-dependent protein kinase 5 is required for release of egress-specific organelles in <italic toggle="yes">plasmodium falciparum</italic>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/9ff6ac7be22a4dbebd4235997aee08ce
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Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in <italic toggle="yes">Plasmodium falciparum</italic>

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