title: WITHDRAWN: Toxoplasma gondii virulence factor ROP18 inhibits the host NF-κB pathway by promoting p65 degradation.
abstract: The obligate intracellular parasite Toxoplasma gondii secretes effector molecules into the host cell to modulate host immunity. Previous studies have shown that T. gondii could interfere with host NF-κB signaling to promote their survival, but the effectors of type I strains remain unclear. The polymorphic rhoptry protein ROP18 is a key serine/threonine kinase that phosphorylates host proteins to modulate acute virulence. Our data demonstrated that the N-terminal portion of ROP18 is associated with the dimerization domain of p65. ROP18 phosphorylates p65 at Ser-468 and targets this protein to the ubiquitin-dependent degradation pathway. The kinase activity of ROP18 is required for p65 degradation and suppresses NF-κB activation. Consistently, compared with wild-type ROP18 strain, ROP18 kinase-deficient type I parasites displayed a severe inability to inhibit NF-κB, culminating in the enhanced production of IL-6, IL-12, and TNF-α in infected macrophages. In addition, studies have shown that transgenic parasites carrying kinase-deficient ROP18 induce M1-biased activation. These results demonstrate for the first time that the virulence factor ROP18 in T. gondii type I strains is responsible for inhibiting the host NF-κB pathway and for suppressing proinflammatory cytokine expression, thus providing a survival advantage to the infectious agent.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Du
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.forename: Lijian
authors.initials: L
authors.lastname: Chen
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Shen
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Cheng
authors.forename: Zhongru
authors.initials: Z
authors.lastname: Jiang
authors.forename: Aimei
authors.initials: A
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Deyong
authors.initials: D
authors.lastname: Chu
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.forename: Qingli
authors.initials: Q
authors.lastname: Luo
authors.forename: He
authors.initials: H
authors.lastname: Chen
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wan
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Xiucai
authors.initials: X
authors.lastname: Xu
authors.forename: Jilong
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005260:Female; D057809:HEK293 Cells; D006790:Host-Parasite Interactions; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014122:Toxoplasma / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D015800:Protozoan Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D018664:Interleukin-12; D012694:Serine; D017346:Protein Serine-Threonine Kinases; C556793:ROP18 protein, Toxoplasma gondii
keywords: Cell Biology; NF-kB Transcription Factor; NF-κB (NF-KB); Parasite; Parasitology; Pathogenesis; Signal Transduction