<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors

ABSTRACT The protozoan parasite Toxoplasma gondii secretes proteins from specialized organelles, the rhoptries, and dense granules, which are involved in the modulation of host cell processes. Dense granule protein GRA15 activates the nuclear factor kappa B (NF-κB) pathway, which plays an important...

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Autores principales:	Lamba Omar Sangaré, Ninghan Yang, Eleni K. Konstantinou, Diana Lu, Debanjan Mukhopadhyay, Lucy H. Young, Jeroen P. J. Saeij
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	NF-κB pathway TRAF2 TRAF6 Toxoplasma gondii host-pathogen interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/934f0f06ec9841a6a0fd1c9bec355d73
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spelling	oai:doaj.org-article:934f0f06ec9841a6a0fd1c9bec355d732021-11-15T16:22:10Z<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors10.1128/mBio.00808-192150-7511https://doaj.org/article/934f0f06ec9841a6a0fd1c9bec355d732019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00808-19https://doaj.org/toc/2150-7511ABSTRACT The protozoan parasite Toxoplasma gondii secretes proteins from specialized organelles, the rhoptries, and dense granules, which are involved in the modulation of host cell processes. Dense granule protein GRA15 activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. Exactly how GRA15 activates the NF-κB pathway is unknown. Here we show that GRA15 interacts with tumor necrosis factor receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. We identified several TRAF binding sites in the GRA15 amino acid sequence and showed that these are involved in NF-κB activation. Furthermore, a TRAF2 knockout cell line has impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation. IMPORTANCE The parasite Toxoplasma can cause birth defects and severe disease in immunosuppressed patients. Strain differences in pathogenicity exist, and these differences are due to polymorphic effector proteins that Toxoplasma secretes into the host cell to coopt host cell functions. The effector protein GRA15 of some Toxoplasma strains activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. We show that GRA15 interacts with TNF receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. Deletion of TRAF-binding sites in GRA15 greatly reduces its ability to activate the NF-κB pathway, and TRAF2 knockout cells have impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation.Lamba Omar SangaréNinghan YangEleni K. KonstantinouDiana LuDebanjan MukhopadhyayLucy H. YoungJeroen P. J. SaeijAmerican Society for MicrobiologyarticleNF-κB pathwayTRAF2TRAF6Toxoplasma gondiihost-pathogen interactionsMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	NF-κB pathway TRAF2 TRAF6 Toxoplasma gondii host-pathogen interactions Microbiology QR1-502
spellingShingle	NF-κB pathway TRAF2 TRAF6 Toxoplasma gondii host-pathogen interactions Microbiology QR1-502 Lamba Omar Sangaré Ninghan Yang Eleni K. Konstantinou Diana Lu Debanjan Mukhopadhyay Lucy H. Young Jeroen P. J. Saeij <italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
description	ABSTRACT The protozoan parasite Toxoplasma gondii secretes proteins from specialized organelles, the rhoptries, and dense granules, which are involved in the modulation of host cell processes. Dense granule protein GRA15 activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. Exactly how GRA15 activates the NF-κB pathway is unknown. Here we show that GRA15 interacts with tumor necrosis factor receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. We identified several TRAF binding sites in the GRA15 amino acid sequence and showed that these are involved in NF-κB activation. Furthermore, a TRAF2 knockout cell line has impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation. IMPORTANCE The parasite Toxoplasma can cause birth defects and severe disease in immunosuppressed patients. Strain differences in pathogenicity exist, and these differences are due to polymorphic effector proteins that Toxoplasma secretes into the host cell to coopt host cell functions. The effector protein GRA15 of some Toxoplasma strains activates the nuclear factor kappa B (NF-κB) pathway, which plays an important role in cell death, innate immunity, and inflammation. We show that GRA15 interacts with TNF receptor-associated factors (TRAFs), which are adaptor proteins functioning upstream of the NF-κB transcription factor. Deletion of TRAF-binding sites in GRA15 greatly reduces its ability to activate the NF-κB pathway, and TRAF2 knockout cells have impaired GRA15-mediated NF-κB activation. Thus, we determined the mechanism for GRA15-dependent NF-κB activation.
format	article
author	Lamba Omar Sangaré Ninghan Yang Eleni K. Konstantinou Diana Lu Debanjan Mukhopadhyay Lucy H. Young Jeroen P. J. Saeij
author_facet	Lamba Omar Sangaré Ninghan Yang Eleni K. Konstantinou Diana Lu Debanjan Mukhopadhyay Lucy H. Young Jeroen P. J. Saeij
author_sort	Lamba Omar Sangaré
title	<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
title_short	<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
title_full	<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
title_fullStr	<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
title_full_unstemmed	<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors
title_sort	<italic toggle="yes">toxoplasma</italic> gra15 activates the nf-κb pathway through interactions with tnf receptor-associated factors
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/934f0f06ec9841a6a0fd1c9bec355d73
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<italic toggle="yes">Toxoplasma</italic> GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors

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