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ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18

Yamamoto, Masahiro
Ma, Ji Su
Kamiyama, Naganori
Saiga, Hiroyuki
Kubo, Emi
Kimura, Taishi
Okamoto, Toru
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Published in The journal of experimental medicine. 2011, vol. 208, no. 7, p. 1533-46
Abstract The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum-bound transcription factor ATF6β. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6β-dependent pathogenicity by interacting with ATF6β and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6β and for parasite virulence. Consistent with a key role for ATF6β in resistance against this intracellular pathogen, ATF6β-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6β-dependent immune responses is a novel pathogenic mechanism induced by ROP18.
Keywords Activating Transcription Factor 6/deficiency/genetics/immunology/metabolismAnimalsAnimals, Genetically ModifiedGene Knockout TechniquesGenes, ProtozoanHost-Parasite Interactions/immunology/physiologyHypersensitivity, Immediate/etiologyMiceMice, Inbred BALB CMice, Inbred ICRMice, KnockoutProtein-Serine-Threonine Kinases/genetics/toxicityToxoplasma/enzymology/genetics/pathogenicityToxoplasmosis, Animal/etiology/immunologyVirulence/physiologyVirulence Factors/genetics/toxicity
PMID: 21670204
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Article (Accepted version) (2.1 MB) - public document Free access
Research group Biologie d'un parasite intracellulaire obligatoire (773)
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YAMAMOTO, Masahiro et al. ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18. In: Journal of Experimental Medicine, 2011, vol. 208, n° 7, p. 1533-46. doi: 10.1084/jem.20101660 https://archive-ouverte.unige.ch/unige:17847

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Deposited on : 2011-12-20

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