title: ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18.
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.
authors.affiliation: Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Ji Su
authors.initials: JS
authors.lastname: Ma
authors.forename: Christina
authors.initials: C
authors.lastname: Mueller
authors.forename: Naganori
authors.initials: N
authors.lastname: Kamiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saiga
authors.forename: Emi
authors.initials: E
authors.lastname: Kubo
authors.forename: Taishi
authors.initials: T
authors.lastname: Kimura
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.forename: Megumi
authors.initials: M
authors.lastname: Okuyama
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.forename: Kisaburo
authors.initials: K
authors.lastname: Nagamune
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Matsuura
authors.forename: Dominique
authors.initials: D
authors.lastname: Soldati-Favre
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D051702:Activating Transcription Factor 6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D055786:Gene Knockout Techniques; D017125:Genes, Protozoan; D006790:Host-Parasite Interactions / Q000276:immunology / Q000502:physiology; D006969:Hypersensitivity, Immediate / Q000209:etiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000633:toxicity*; D015800:Protozoan Proteins; D014122:Toxoplasma / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D014124:Toxoplasmosis, Animal / Q000209:etiology / Q000276:immunology; D014774:Virulence / Q000502:physiology; D037521:Virulence Factors / Q000235:genetics / Q000633:toxicity*
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D015800:Protozoan Proteins; D037521:Virulence Factors; D017346:Protein Serine-Threonine Kinases; C556793:ROP18 protein, Toxoplasma gondii