A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>

ABSTRACT Apicomplexan parasites cause a variety of important infectious diseases, including malaria, toxoplasma encephalitis, and severe diarrhea due to Cryptosporidium. Most apicomplexans depend on an organelle called the apicoplast which is derived from a red algal endosymbiont. The apicoplast is...

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Autores principales:	Justin D. Fellows, Michael J. Cipriano, Swati Agrawal, Boris Striepen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Toxoplasma apicomplexan parasites apicoplast chloroplast organelle protein import ubiquitin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/6c5f476588964f2392f13d54fb255032
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spelling	oai:doaj.org-article:6c5f476588964f2392f13d54fb2550322021-11-15T15:51:29ZA Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>10.1128/mBio.00950-172150-7511https://doaj.org/article/6c5f476588964f2392f13d54fb2550322017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00950-17https://doaj.org/toc/2150-7511ABSTRACT Apicomplexan parasites cause a variety of important infectious diseases, including malaria, toxoplasma encephalitis, and severe diarrhea due to Cryptosporidium. Most apicomplexans depend on an organelle called the apicoplast which is derived from a red algal endosymbiont. The apicoplast is essential for the parasite as the compartment of fatty acid, heme, and isoprenoid biosynthesis. The majority of the approximate 500 apicoplast proteins are nucleus encoded and have to be imported across the four membranes that surround the apicoplast. Import across the second outermost membrane of the apicoplast, the periplastid membrane, depends on an apicoplast-specific endoplasmic reticulum-associated protein degradation (ERAD) complex and on enzymes of the associated ubiquitination cascade. However, identification of an apicoplast ubiquitin associated with this machinery has long been elusive. Here we identify a plastid ubiquitin-like protein (PUBL), an apicoplast protein that is derived from a ubiquitin ancestor but that has significantly changed in its primary sequence. PUBL is distinct from known ubiquitin-like proteins, and phylogenomic analyses suggest a clade specific to apicomplexans. We demonstrate that PUBL and the AAA ATPase CDC48AP both act to translocate apicoplast proteins across the periplastid membrane during protein import. Conditional null mutants and genetic complementation show that both proteins are critical for this process and for parasite survival. PUBL residues homologous to those that are required for ubiquitin conjugation onto target proteins are essential for this function, while those required for polyubiquitination and preprotein processing are dispensable. Our experiments provide a mechanistic understanding of the molecular machinery that drives protein import across the membranes of the apicoplast. IMPORTANCE Apicomplexan parasites are responsible for important human diseases. There are no effective vaccines for use in humans, and drug treatment faces multiple challenges, including emerging resistance, lack of efficacy across the lifecycle, and adverse drug effects. The apicoplast is a promising target for novel treatments: this chloroplast-like organelle is derived from an algal symbiont, is absent from the host, and is essential for parasite growth and pathogenesis. We use Toxoplasma gondii as a model to study the apicoplast due to its strong genetic tools and established functional assays. We identify a plastid ubiquitin-like protein (PUBL) which is a novel ubiquitin-like protein and demonstrate its importance and that of the motor protein CDC48AP for apicoplast protein import. These findings broaden our understanding of the evolution and mechanistic workings of a unique parasite organelle and may lead to new opportunities for treatments against important human pathogens.Justin D. FellowsMichael J. CiprianoSwati AgrawalBoris StriepenAmerican Society for MicrobiologyarticleToxoplasmaapicomplexan parasitesapicoplastchloroplastorganelle protein importubiquitinMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Toxoplasma apicomplexan parasites apicoplast chloroplast organelle protein import ubiquitin Microbiology QR1-502
spellingShingle	Toxoplasma apicomplexan parasites apicoplast chloroplast organelle protein import ubiquitin Microbiology QR1-502 Justin D. Fellows Michael J. Cipriano Swati Agrawal Boris Striepen A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>
description	ABSTRACT Apicomplexan parasites cause a variety of important infectious diseases, including malaria, toxoplasma encephalitis, and severe diarrhea due to Cryptosporidium. Most apicomplexans depend on an organelle called the apicoplast which is derived from a red algal endosymbiont. The apicoplast is essential for the parasite as the compartment of fatty acid, heme, and isoprenoid biosynthesis. The majority of the approximate 500 apicoplast proteins are nucleus encoded and have to be imported across the four membranes that surround the apicoplast. Import across the second outermost membrane of the apicoplast, the periplastid membrane, depends on an apicoplast-specific endoplasmic reticulum-associated protein degradation (ERAD) complex and on enzymes of the associated ubiquitination cascade. However, identification of an apicoplast ubiquitin associated with this machinery has long been elusive. Here we identify a plastid ubiquitin-like protein (PUBL), an apicoplast protein that is derived from a ubiquitin ancestor but that has significantly changed in its primary sequence. PUBL is distinct from known ubiquitin-like proteins, and phylogenomic analyses suggest a clade specific to apicomplexans. We demonstrate that PUBL and the AAA ATPase CDC48AP both act to translocate apicoplast proteins across the periplastid membrane during protein import. Conditional null mutants and genetic complementation show that both proteins are critical for this process and for parasite survival. PUBL residues homologous to those that are required for ubiquitin conjugation onto target proteins are essential for this function, while those required for polyubiquitination and preprotein processing are dispensable. Our experiments provide a mechanistic understanding of the molecular machinery that drives protein import across the membranes of the apicoplast. IMPORTANCE Apicomplexan parasites are responsible for important human diseases. There are no effective vaccines for use in humans, and drug treatment faces multiple challenges, including emerging resistance, lack of efficacy across the lifecycle, and adverse drug effects. The apicoplast is a promising target for novel treatments: this chloroplast-like organelle is derived from an algal symbiont, is absent from the host, and is essential for parasite growth and pathogenesis. We use Toxoplasma gondii as a model to study the apicoplast due to its strong genetic tools and established functional assays. We identify a plastid ubiquitin-like protein (PUBL) which is a novel ubiquitin-like protein and demonstrate its importance and that of the motor protein CDC48AP for apicoplast protein import. These findings broaden our understanding of the evolution and mechanistic workings of a unique parasite organelle and may lead to new opportunities for treatments against important human pathogens.
format	article
author	Justin D. Fellows Michael J. Cipriano Swati Agrawal Boris Striepen
author_facet	Justin D. Fellows Michael J. Cipriano Swati Agrawal Boris Striepen
author_sort	Justin D. Fellows
title	A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>
title_short	A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>
title_full	A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>
title_fullStr	A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>
title_full_unstemmed	A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>
title_sort	plastid protein that evolved from ubiquitin and is required for apicoplast protein import in <italic toggle="yes">toxoplasma gondii</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/6c5f476588964f2392f13d54fb255032
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A Plastid Protein That Evolved from Ubiquitin and Is Required for Apicoplast Protein Import in <italic toggle="yes">Toxoplasma gondii</italic>

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