Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors

Lamba Omar Sangaré, Ninghan Yang, Eleni K. Konstantinou, Diana Lu, Debanjan Mukhopadhyay, Lucy H. Young, Jeroen Saeij

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalmBio
Volume10
Issue number4
DOIs
StatePublished - Jul 16 2019

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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
NF-kappa B
Toxoplasma
TNF Receptor-Associated Factor 2
Proteins
Innate Immunity
Parasites
Cell Death
Transcription Factors
Binding Sites
Inflammation
Organelles
Virulence
Amino Acid Sequence

Keywords

  • host-pathogen interactions
  • NF-κB pathway
  • Toxoplasma gondii
  • TRAF2
  • TRAF6

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Sangaré, L. O., Yang, N., Konstantinou, E. K., Lu, D., Mukhopadhyay, D., Young, L. H., & Saeij, J. (2019). Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors. mBio, 10(4). https://doi.org/10.1128/mBio.00808-19

Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors. / Sangaré, Lamba Omar; Yang, Ninghan; Konstantinou, Eleni K.; Lu, Diana; Mukhopadhyay, Debanjan; Young, Lucy H.; Saeij, Jeroen.

In: mBio, Vol. 10, No. 4, 16.07.2019.

Research output: Contribution to journalArticle

Sangaré LO, Yang N, Konstantinou EK, Lu D, Mukhopadhyay D, Young LH et al. Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors. mBio. 2019 Jul 16;10(4). https://doi.org/10.1128/mBio.00808-19
Sangaré, Lamba Omar ; Yang, Ninghan ; Konstantinou, Eleni K. ; Lu, Diana ; Mukhopadhyay, Debanjan ; Young, Lucy H. ; Saeij, Jeroen. / Toxoplasma GRA15 Activates the NF-κB Pathway through Interactions with TNF Receptor-Associated Factors. In: mBio. 2019 ; Vol. 10, No. 4.
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AB - 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.

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