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Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins
Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorou...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700025/ https://www.ncbi.nlm.nih.gov/pubmed/34898650 http://dx.doi.org/10.1371/journal.ppat.1010138 |
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author | Rivera-Cuevas, Yolanda Mayoral, Joshua Di Cristina, Manlio Lawrence, Anna-Lisa E. Olafsson, Einar B. Patel, Romir K. Thornhill, Dishari Waldman, Benjamin S. Ono, Akira Sexton, Jonathan Z. Lourido, Sebastian Weiss, Louis M. Carruthers, Vern B. |
author_facet | Rivera-Cuevas, Yolanda Mayoral, Joshua Di Cristina, Manlio Lawrence, Anna-Lisa E. Olafsson, Einar B. Patel, Romir K. Thornhill, Dishari Waldman, Benjamin S. Ono, Akira Sexton, Jonathan Z. Lourido, Sebastian Weiss, Louis M. Carruthers, Vern B. |
author_sort | Rivera-Cuevas, Yolanda |
collection | PubMed |
description | Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorous vacuole (PV), the parasite must acquire resources across the limiting membrane of its replicative niche, which is decorated with parasite proteins including those secreted from dense granules. We discovered a role for the host Endosomal Sorting Complex Required for Transport (ESCRT) machinery in host cytosolic protein uptake by T. gondii by disrupting host ESCRT function. We identified the transmembrane dense granule protein TgGRA14, which contains motifs homologous to the late domain motifs of HIV-1 Gag, as a candidate for the recruitment of the host ESCRT machinery to the PV membrane. Using an HIV-1 virus-like particle (VLP) release assay, we found that the motif-containing portion of TgGRA14 is sufficient to substitute for HIV-1 Gag late domain to mediate ESCRT-dependent VLP budding. We also show that TgGRA14 is proximal to and interacts with host ESCRT components and other dense granule proteins during infection. Furthermore, analysis of TgGRA14-deficient parasites revealed a marked reduction in ingestion of a host cytosolic protein compared to WT parasites. Thus, we propose a model in which T. gondii recruits the host ESCRT machinery to the PV where it can interact with TgGRA14 for the internalization of host cytosolic proteins across the PV membrane (PVM). These findings provide new insight into how T. gondii accesses contents of the host cytosol by exploiting a key pathway for vesicular budding and membrane scission. |
format | Online Article Text |
id | pubmed-8700025 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-87000252021-12-24 Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins Rivera-Cuevas, Yolanda Mayoral, Joshua Di Cristina, Manlio Lawrence, Anna-Lisa E. Olafsson, Einar B. Patel, Romir K. Thornhill, Dishari Waldman, Benjamin S. Ono, Akira Sexton, Jonathan Z. Lourido, Sebastian Weiss, Louis M. Carruthers, Vern B. PLoS Pathog Research Article Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorous vacuole (PV), the parasite must acquire resources across the limiting membrane of its replicative niche, which is decorated with parasite proteins including those secreted from dense granules. We discovered a role for the host Endosomal Sorting Complex Required for Transport (ESCRT) machinery in host cytosolic protein uptake by T. gondii by disrupting host ESCRT function. We identified the transmembrane dense granule protein TgGRA14, which contains motifs homologous to the late domain motifs of HIV-1 Gag, as a candidate for the recruitment of the host ESCRT machinery to the PV membrane. Using an HIV-1 virus-like particle (VLP) release assay, we found that the motif-containing portion of TgGRA14 is sufficient to substitute for HIV-1 Gag late domain to mediate ESCRT-dependent VLP budding. We also show that TgGRA14 is proximal to and interacts with host ESCRT components and other dense granule proteins during infection. Furthermore, analysis of TgGRA14-deficient parasites revealed a marked reduction in ingestion of a host cytosolic protein compared to WT parasites. Thus, we propose a model in which T. gondii recruits the host ESCRT machinery to the PV where it can interact with TgGRA14 for the internalization of host cytosolic proteins across the PV membrane (PVM). These findings provide new insight into how T. gondii accesses contents of the host cytosol by exploiting a key pathway for vesicular budding and membrane scission. Public Library of Science 2021-12-13 /pmc/articles/PMC8700025/ /pubmed/34898650 http://dx.doi.org/10.1371/journal.ppat.1010138 Text en © 2021 Rivera-Cuevas et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Rivera-Cuevas, Yolanda Mayoral, Joshua Di Cristina, Manlio Lawrence, Anna-Lisa E. Olafsson, Einar B. Patel, Romir K. Thornhill, Dishari Waldman, Benjamin S. Ono, Akira Sexton, Jonathan Z. Lourido, Sebastian Weiss, Louis M. Carruthers, Vern B. Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins |
title | Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins |
title_full | Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins |
title_fullStr | Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins |
title_full_unstemmed | Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins |
title_short | Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins |
title_sort | toxoplasma gondii exploits the host escrt machinery for parasite uptake of host cytosolic proteins |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700025/ https://www.ncbi.nlm.nih.gov/pubmed/34898650 http://dx.doi.org/10.1371/journal.ppat.1010138 |
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