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Caspase-11 regulates cell migration by promoting Aip1–Cofilin-mediated actin depolymerization

An Addendum to this article was published on 01 April 2007

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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Figure 1: Caspase-11−/− splenocytes and peritoneal macrophages are defective in cell migration in vitro and in vivo.
Figure 2: Identification of Aip1 as a caspase-11-interacting protein by affinity purification.
Figure 3: Aip1 RNAi cells are defective in cell migration in vitro.
Figure 4: Caspase-11 regulates actin dynamics in vivo.
Figure 5: Caspase-11 regulates actin depolymerization in vitro.
Figure 6: Cofilin levels are upregulated in caspase-11−/− spleen and Aip1 RNAi cells.
Figure 7: A schematic representation of a model for caspase-11-mediated cofilin- and Aip1-dependent actin depolymerization.

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References

  1. Cryns, V. & Yuan, J. Proteases to die for. Genes Dev. 12, 1551–1570 (1998).

    Article  CAS  Google Scholar 

  2. Wang, S. et al. Identification and characterization of Ich-3, a member of the interleukin-1β converting enzyme (ICE)/Ced-3 family and an upstream regulator of ICE. J. Biol. Chem. 271, 20580–20587 (1996).

    Article  CAS  Google Scholar 

  3. Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998).

    Article  CAS  Google Scholar 

  4. Kang, S. J. et al. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 149, 613–622 (2000).

    Article  CAS  Google Scholar 

  5. Kang, S. J., Wang, S., Kuida, K. & Yuan, J. Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response. Cell Death Differ. 9, 1115–1125 (2002).

    Article  CAS  Google Scholar 

  6. Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

    Article  CAS  Google Scholar 

  7. Bamburg, J. R. Proteins of the ADF/cofilin family: essential regulators of actin dynamics. Annu. Rev. Cell Dev. Biol. 15, 185–230 (1999).

    Article  CAS  Google Scholar 

  8. Ono, S. Regulation of actin filament dynamics by actin depolymerizing factor/cofilin and actin-interacting protein 1: new blades for twisted filaments. Biochemistry 42, 13363–13370 (2003).

    Article  CAS  Google Scholar 

  9. Okada, K. et al. Xenopus actin-interacting protein 1 (XAip1) enhances cofilin fragmentation of filaments by capping filament ends. J. Biol. Chem. 277, 43011–43016 (2002).

    Article  CAS  Google Scholar 

  10. Konzok, A. et al. DAip1, a Dictyostelium homologue of the yeast actin-interacting protein 1, is involved in endocytosis, cytokinesis, and motility. J. Cell Biol. 146, 453–464 (1999).

    Article  CAS  Google Scholar 

  11. Geisbrecht, E. R. & Montell, D. J. A role for Drosophila IAP1-mediated caspase inhibition in Rac-dependent cell migration. Cell 118, 111–125 (2004).

    Article  CAS  Google Scholar 

  12. Weninger, W., Crowley, M. A., Manjunath, N. & von Andrian, U. H. Migratory properties of naive, effector, and memory CD8(+) T cells. J. Exp. Med. 194, 953–966 (2001).

    Article  CAS  Google Scholar 

  13. Goodarzi, K., Goodarzi, M., Tager, A. M., Luster, A. D. & von Andrian, U. H. Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nature Immunol. 4, 965–973 (2003).

    Article  CAS  Google Scholar 

  14. Mohri, K., Vorobiev, S., Fedorov, A. A., Almo, S. C. & Ono, S. Identification of functional residues on Caenorhabditis elegans actin-interacting protein 1 (UNC-78) for disassembly of actin depolymerizing factor/cofilin-bound actin filaments. J. Biol. Chem. 279, 31697–31707 (2004).

    Article  CAS  Google Scholar 

  15. Yang, L. V., Radu, C. G., Wang, L., Riedinger, M. & Witte, O. N. Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood 105, 1127–1134 (2005).

    Article  CAS  Google Scholar 

  16. Southwick, F. S., Dabiri, G. A., Paschetto, M. & Zigmond, S. H. Polymorphonuclear leukocyte adherence induces actin polymerization by a transduction pathway which differs from that used by chemoattractants. J. Cell Biol. 109, 1561–1569 (1989).

    Article  CAS  Google Scholar 

  17. Cox, D. et al. Requirements for both Rac1 and Cdc42 in membrane ruffling and phagocytosis in leukocytes. J. Exp. Med. 186, 1487–1494 (1997).

    Article  CAS  Google Scholar 

  18. Rogers, S. L., Wiedemann, U., Stuurman, N. & Vale, R. D. Molecular requirements for actin-based lamella formation in Drosophila S2 cells. J. Cell Biol. 162, 1079–1088 (2003).

    Article  CAS  Google Scholar 

  19. Cramer, L. P. Role of actin-filament disassembly in lamellipodium protrusion in motile cells revealed using the drug jasplakinolide. Curr. Biol. 9, 1095–1105 (1999).

    Article  CAS  Google Scholar 

  20. Dawe, H. R., Minamide, L. S., Bamburg, J. R. & Cramer, L. P. ADF/cofilin controls cell polarity during fibroblast migration. Curr. Biol. 13, 252–257 (2003).

    Article  CAS  Google Scholar 

  21. Heyworth, P. G., Robinson, J. M., Ding, J., Ellis, B. A. & Badwey, J. A. Cofilin undergoes rapid dephosphorylation in stimulated neutrophils and translocates to ruffled membranes enriched in products of the NADPH oxidase complex. Histochem. Cell Biol. 108, 221–233 (1997).

    Article  CAS  Google Scholar 

  22. Bleul, C. C., Fuhlbrigge, R. C., Casasnovas, J. M., Aiuti, A. & Springer, T. A. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J. Exp. Med. 184, 1101–1109 (1996).

    Article  CAS  Google Scholar 

  23. Fujibuchi, T. et al. AIP1/WDR1 supports mitotic cell rounding. Biochem. Biophys. Res. Commun. 327, 268–275 (2005).

    Article  CAS  Google Scholar 

  24. Rodal, A. A., Tetreault, J. W., Lappalainen, P., Drubin, D. G. & Amberg, D. C. Aip1p interacts with cofilin to disassemble actin filaments. J. Cell Biol. 145, 1251–1264 (1999).

    Article  CAS  Google Scholar 

  25. Ferraro, E., Corvaro, M. & Cecconi, F. Physiological and pathological roles of Apaf1 and the apoptosome. J. Cell. Mol. Med. 7, 21–34 (2003).

    Article  CAS  Google Scholar 

  26. Brieher, W. M., Coughlin, M. & Mitchison, T. J. Fascin-mediated propulsion of Listeria monocytogenes independent of frequent nucleation by the Arp2/3 complex. J. Cell Biol. 165, 233–242 (2004).

    Article  CAS  Google Scholar 

  27. Maciver, S. K., Pope, B. J., Whytock, S. & Weeds, A. G. The effect of two actin depolymerizing factors (ADF/cofilins) on actin filament turnover: pH sensitivity of F-actin binding by human ADF, but not of Acanthamoeba actophorin. Eur. J. Biochem. 256, 388–397 (1998).

    Article  CAS  Google Scholar 

  28. Brieher, W. M., Kueh, H. Y., Ballif, B. A. & Mitchison, T. J. Rapid actin monomer-insensitive depolymerization of Listeria actin comet tails by cofilin, coronin, and Aip1. J. Cell Biol. 175, 315–324 (2006).

    Article  CAS  Google Scholar 

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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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Correspondence to Junying Yuan.

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The authors declare no competing financial interests.

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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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