Abstract
In response to invading microorganisms, macrophages engage in phagocytosis and rapidly release reactive oxygen species (ROS), which serve an important microbicidal function. However, how phagocytosis induces ROS production remains largely unknown. CARD9, a caspase-recruitment domain (CARD)-containing protein, is important for resistance to fungal and bacterial infection. The mechanism of CARD9-mediated bacterial clearance is still mostly unknown. Here we show that CARD9 is required for killing intracellular bacteria in macrophages. CARD9 associated with the GDP-dissociation inhibitor LyGDI in phagosomes after bacterial and fungal infection and binding of CARD9 suppressed LyGDI-mediated inhibition of the GTPase Rac1, thereby leading to ROS production and bacterial killing in macrophages. Thus, our studies identify a key pathway that leads to microbe-elicited ROS production.
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Acknowledgements
We thank W. Li and F. Southwick (University of Florida) for GFP–L. monocytogenes, and X. Qin (University of Texas MD Anderson Cancer Center) for the retroviral packaging vector pCGP and pVSV-G. Supported by the National Institutes of Health (RO1AI050848 and R01GM065899 to X.L. and R01GM069572 to Z.S.), the Welch Foundation (Z.S.) and the Leukemia and Lymphoma Society (X.L. and Z.S.).
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W.W., Y.-M.S.H. and L.B. did the experiments; W.W. and X.L. designed the experiments, analyzed the results and wrote the manuscript; and Z.S. provided the reagents and technical advice.
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Wu, W., Hsu, YM., Bi, L. et al. CARD9 facilitates microbe-elicited production of reactive oxygen species by regulating the LyGDI-Rac1 complex. Nat Immunol 10, 1208–1214 (2009). https://doi.org/10.1038/ni.1788
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DOI: https://doi.org/10.1038/ni.1788
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