Abstract
Coordinated regulation of cell migration, cytokine maturation and apoptosis is critical in inflammatory responses. Caspases, a family of cysteine proteases, are known to regulate cytokine maturation and apoptosis. Here, we show that caspase-11, a mammalian pro-inflammatory caspase, regulates cell migration during inflammation. Caspase-11-deficient lymphocytes exhibit a cell-autonomous migration defect in vitro and in vivo. We demonstrate that caspase-11 interacts physically and functionally with actin interacting protein 1 (Aip1), an activator of cofilin-mediated actin depolymerization. The caspase-recruitment domain (CARD) of caspase-11 interacts with the carboxy-terminal WD40 propeller domain of Aip1 to promote cofilin-mediated actin depolymerization. Cells with Aip1 or caspase-11 deficiency exhibit defects in actin dynamics. Using in vitro actin depolymerization assays, we found that caspase-11 and Aip1 work cooperatively to promote cofilin-mediated actin depolymerization. These data demonstrate a novel cell autonomous caspase-mediated mechanism that regulates actin dynamics and mammalian cell migration distinct from the receptor mediated Rho–Rac–Cdc42 pathway.
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Acknowledgements
We thank Q. Shi and R. King for kindly allowing us to use the time-lapse microscope setup and J. Waters in the Nikon Imaging Center of Harvard Medical School for expert help with cell imaging. We thank C. Mahlke for mouse genotyping. We thank M. Boyce, A. Degterev, M. Lipinski and R. Sanchez-Olea for critical reading of this manuscript and members of Yuan laboratory for helpful suggestions during the course of this work. This work was supported in part by a NIH Merit Award (R37 AG12859 to J. Y.).
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J.L. identified Aip1 as a caspase-11 binding protein, and discovered and characterized the defects of caspase-11−/− cells in migration. W.B. and J.L. performed the in vitro actin depolymerization assays. L.S. and J.L. performed the in vivo homing assay. S.J.K. and J.L. examined the composition of caspase-11−/− immune system. H.Z. generated anti-Aip1 antibodies. J.L. and J.Y. wrote the paper. J.Y. directed the work. All authors discussed the results and commented on the manuscript.
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Li, J., Brieher, W., Scimone, M. et al. Caspase-11 regulates cell migration by promoting Aip1–Cofilin-mediated actin depolymerization. Nat Cell Biol 9, 276–286 (2007). https://doi.org/10.1038/ncb1541
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DOI: https://doi.org/10.1038/ncb1541
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