@article{616ddc5d2c9e4a4e9af5e19d32f24491,
title = "Phosphorylation of immunity-related GTPases by a toxoplasma gondii-secreted kinase promotes macrophage survival and virulence",
abstract = "Macrophages are specialized to detect and destroy intracellular microbes and yet a number of pathogens have evolved to exploit this hostile niche. Here we demonstrate that the obligate intracellular parasite Toxoplasma gondii disarms macrophage innate clearance mechanisms by secreting a serine threonine kinase called ROP18, which binds to and phosphorylates immunity-related GTPases (IRGs). Substrate profiling of ROP18 revealed a preference for a conserved motif within switch region I of the GTPase domain, a modification predicted to disrupt IRG function. Consistent with this, expression of ROP18 was both necessary and sufficient to block recruitment of Irgb6, which was in turn required for parasite destruction. ROP18 phosphorylation of IRGs prevented clearance within inflammatory monocytes and IFN-γ-activated macrophages, conferring parasite survival in vivo and promoting virulence. IRGs are implicated in clearance of a variety of intracellular pathogens, suggesting that other virulence factors may similarly thwart this innate cellular defense mechanism.",
author = "Fentress, {Sarah J.} and Behnke, {Michael S.} and Dunay, {Ildiko R.} and Mona Mashayekhi and Rommereim, {Leah M.} and Fox, {Barbara A.} and Bzik, {David J.} and Taylor, {Gregory A.} and Turk, {Benjamin E.} and Lichti, {Cheryl F.} and Townsend, {R. Reid} and Wei Qiu and Raymond Hui and Beatty, {Wandy L.} and Sibley, {L. David}",
note = "Funding Information: We thank J. Howard for sharing unpublished data, G. Yap and N. Tolia for discussions, K. Tang, P. Erdmann-Gilmore, A.E. Davis, and J. Nawas for technical assistance, and M.F. Cesbron-Delauw, J. Boothroyd, S. Kaufmann, and J. Coers for antibodies. This work was supported by grants from the National Institutes of Health (NIH; AI036629 and AI084243 to L.D.S., AI57831 to G.A.T., AI073142 to D.J.B, amd GM079498 to B.E.T.) and a VA Merit review grant (G.A.T.). The mass spectrometry at Washington University was supported by supported by NIH grants P41RR000954 and UL1 RR024992 from the National Center for Research Resources. S.J.F. was partially supported by a Morse Berg Fellowship, Washington University. I.R.D. was supported by a fellowship from the Deutsche Forschungsgemeinschaft, Germany. S.J.F. designed and performed the majority of experiments, analyzed the data, generated the figures, and contributed to writing the manuscript. I.R.D. and M.M. assisted with the in vivo experiments and performed the flow cytometry analysis, M.S.B. and B.E.T. performed the motif analyses, L.M.R, B.A.F., and D.J.B. generated and validated the Δrop18 knockout, W.L.B. performed the EM experiments, G.A.T. provided key reagents and insight into IRG function, W.Q., R.H., C.F.L., and R.R.T. performed the MS experiments, and L.D.S. supervised the studies and contributed to design and analyses of the experiments, and writing/editing of the manuscript. All authors approved the manuscript. ",
year = "2010",
month = dec,
day = "16",
doi = "10.1016/j.chom.2010.11.005",
language = "English (US)",
volume = "8",
pages = "484--495",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "6",
}