Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.

Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lyso...

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Autores principales:	Luis Muniz-Feliciano, Jennifer Van Grol, Jose-Andres C Portillo, Lloyd Liew, Bing Liu, Cathleen R Carlin, Vern B Carruthers, Stephen Matthews, Carlos S Subauste
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/a7e60ba2904940118547708938ad7a9e
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spelling	oai:doaj.org-article:a7e60ba2904940118547708938ad7a9e2021-11-18T06:07:13ZToxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.1553-73661553-737410.1371/journal.ppat.1003809https://doaj.org/article/a7e60ba2904940118547708938ad7a9e2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24367261/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival.Luis Muniz-FelicianoJennifer Van GrolJose-Andres C PortilloLloyd LiewBing LiuCathleen R CarlinVern B CarruthersStephen MatthewsCarlos S SubaustePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 12, p e1003809 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Luis Muniz-Feliciano Jennifer Van Grol Jose-Andres C Portillo Lloyd Liew Bing Liu Cathleen R Carlin Vern B Carruthers Stephen Matthews Carlos S Subauste Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.
description	Toxoplasma gondii resides in an intracellular compartment (parasitophorous vacuole) that excludes transmembrane molecules required for endosome-lysosome recruitment. Thus, the parasite survives by avoiding lysosomal degradation. However, autophagy can re-route the parasitophorous vacuole to the lysosomes and cause parasite killing. This raises the possibility that T. gondii may deploy a strategy to prevent autophagic targeting to maintain the non-fusogenic nature of the vacuole. We report that T. gondii activated EGFR in endothelial cells, retinal pigment epithelial cells and microglia. Blockade of EGFR or its downstream molecule, Akt, caused targeting of the parasite by LC3(+) structures, vacuole-lysosomal fusion, lysosomal degradation and killing of the parasite that were dependent on the autophagy proteins Atg7 and Beclin 1. Disassembly of GPCR or inhibition of metalloproteinases did not prevent EGFR-Akt activation. T. gondii micronemal proteins (MICs) containing EGF domains (EGF-MICs; MIC3 and MIC6) appeared to promote EGFR activation. Parasites defective in EGF-MICs (MIC1 ko, deficient in MIC1 and secretion of MIC6; MIC3 ko, deficient in MIC3; and MIC1-3 ko, deficient in MIC1, MIC3 and secretion of MIC6) caused impaired EGFR-Akt activation and recombinant EGF-MICs (MIC3 and MIC6) caused EGFR-Akt activation. In cells treated with autophagy stimulators (CD154, rapamycin) EGFR signaling inhibited LC3 accumulation around the parasite. Moreover, increased LC3 accumulation and parasite killing were noted in CD154-activated cells infected with MIC1-3 ko parasites. Finally, recombinant MIC3 and MIC6 inhibited parasite killing triggered by CD154 particularly against MIC1-3 ko parasites. Thus, our findings identified EGFR activation as a strategy used by T. gondii to maintain the non-fusogenic nature of the parasitophorous vacuole and suggest that EGF-MICs have a novel role in affecting signaling in host cells to promote parasite survival.
format	article
author	Luis Muniz-Feliciano Jennifer Van Grol Jose-Andres C Portillo Lloyd Liew Bing Liu Cathleen R Carlin Vern B Carruthers Stephen Matthews Carlos S Subauste
author_facet	Luis Muniz-Feliciano Jennifer Van Grol Jose-Andres C Portillo Lloyd Liew Bing Liu Cathleen R Carlin Vern B Carruthers Stephen Matthews Carlos S Subauste
author_sort	Luis Muniz-Feliciano
title	Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.
title_short	Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.
title_full	Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.
title_fullStr	Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.
title_full_unstemmed	Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.
title_sort	toxoplasma gondii-induced activation of egfr prevents autophagy protein-mediated killing of the parasite.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a7e60ba2904940118547708938ad7a9e
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Toxoplasma gondii-induced activation of EGFR prevents autophagy protein-mediated killing of the parasite.

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