Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion

We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of...

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Autores principales:	Anja C. Schlott, Ellen Knuepfer, Judith L. Green, Philip Hobson, Aaron J. Borg, Julia Morales-Sanfrutos, Abigail J. Perrin, Catherine Maclachlan, Lucy M. Collinson, Ambrosius P. Snijders, Edward W. Tate, Anthony A. Holder
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5fbf8e9a9f734a64b495f33819b59ac8
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spelling	oai:doaj.org-article:5fbf8e9a9f734a64b495f33819b59ac82021-11-04T05:33:02ZInhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion1544-91731545-7885https://doaj.org/article/5fbf8e9a9f734a64b495f33819b59ac82021-10-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544853/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of “pseudoschizonts,” which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition. Understanding the essential factors needed for malaria parasite development could help us find new therapeutic targets. This study reveals that N-myristoylation is a posttranslational modification of proteins essential for the parasites’ growth and their invasion of red blood cells.Anja C. SchlottEllen KnuepferJudith L. GreenPhilip HobsonAaron J. BorgJulia Morales-SanfrutosAbigail J. PerrinCatherine MaclachlanLucy M. CollinsonAmbrosius P. SnijdersEdward W. TateAnthony A. HolderPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 19, Iss 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Anja C. Schlott Ellen Knuepfer Judith L. Green Philip Hobson Aaron J. Borg Julia Morales-Sanfrutos Abigail J. Perrin Catherine Maclachlan Lucy M. Collinson Ambrosius P. Snijders Edward W. Tate Anthony A. Holder Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion
description	We have combined chemical biology and genetic modification approaches to investigate the importance of protein myristoylation in the human malaria parasite, Plasmodium falciparum. Parasite treatment during schizogony in the last 10 to 15 hours of the erythrocytic cycle with IMP-1002, an inhibitor of N-myristoyl transferase (NMT), led to a significant blockade in parasite egress from the infected erythrocyte. Two rhoptry proteins were mislocalized in the cell, suggesting that rhoptry function is disrupted. We identified 16 NMT substrates for which myristoylation was significantly reduced by NMT inhibitor (NMTi) treatment, and, of these, 6 proteins were substantially reduced in abundance. In a viability screen, we showed that for 4 of these proteins replacement of the N-terminal glycine with alanine to prevent myristoylation had a substantial effect on parasite fitness. In detailed studies of one NMT substrate, glideosome-associated protein 45 (GAP45), loss of myristoylation had no impact on protein location or glideosome assembly, in contrast to the disruption caused by GAP45 gene deletion, but GAP45 myristoylation was essential for erythrocyte invasion. Therefore, there are at least 3 mechanisms by which inhibition of NMT can disrupt parasite development and growth: early in parasite development, leading to the inhibition of schizogony and formation of “pseudoschizonts,” which has been described previously; at the end of schizogony, with disruption of rhoptry formation, merozoite development and egress from the infected erythrocyte; and at invasion, when impairment of motor complex function prevents invasion of new erythrocytes. These results underline the importance of P. falciparum NMT as a drug target because of the pleiotropic effect of its inhibition. Understanding the essential factors needed for malaria parasite development could help us find new therapeutic targets. This study reveals that N-myristoylation is a posttranslational modification of proteins essential for the parasites’ growth and their invasion of red blood cells.
format	article
author	Anja C. Schlott Ellen Knuepfer Judith L. Green Philip Hobson Aaron J. Borg Julia Morales-Sanfrutos Abigail J. Perrin Catherine Maclachlan Lucy M. Collinson Ambrosius P. Snijders Edward W. Tate Anthony A. Holder
author_facet	Anja C. Schlott Ellen Knuepfer Judith L. Green Philip Hobson Aaron J. Borg Julia Morales-Sanfrutos Abigail J. Perrin Catherine Maclachlan Lucy M. Collinson Ambrosius P. Snijders Edward W. Tate Anthony A. Holder
author_sort	Anja C. Schlott
title	Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion
title_short	Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion
title_full	Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion
title_fullStr	Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion
title_full_unstemmed	Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion
title_sort	inhibition of protein n-myristoylation blocks plasmodium falciparum intraerythrocytic development, egress and invasion
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5fbf8e9a9f734a64b495f33819b59ac8
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Inhibition of protein N-myristoylation blocks Plasmodium falciparum intraerythrocytic development, egress and invasion

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