Article | Published:

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

Nature Cell Biology volume 9, pages 276286 (2007) | Download Citation

Subjects

  • 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Proteases to die for. Genes Dev. 12, 1551–1570 (1998).

  2. 2.

    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).

  3. 3.

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

  4. 4.

    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).

  5. 5.

    , , & Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response. Cell Death Differ. 9, 1115–1125 (2002).

  6. 6.

    & Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

  7. 7.

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

  8. 8.

    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).

  9. 9.

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

  10. 10.

    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).

  11. 11.

    & A role for Drosophila IAP1-mediated caspase inhibition in Rac-dependent cell migration. Cell 118, 111–125 (2004).

  12. 12.

    , , & Migratory properties of naive, effector, and memory CD8(+) T cells. J. Exp. Med. 194, 953–966 (2001).

  13. 13.

    , , , & Leukotriene B4 and BLT1 control cytotoxic effector T cell recruitment to inflamed tissues. Nature Immunol. 4, 965–973 (2003).

  14. 14.

    , , , & 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).

  15. 15.

    , , , & Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A. Blood 105, 1127–1134 (2005).

  16. 16.

    , , & Polymorphonuclear leukocyte adherence induces actin polymerization by a transduction pathway which differs from that used by chemoattractants. J. Cell Biol. 109, 1561–1569 (1989).

  17. 17.

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

  18. 18.

    , , & Molecular requirements for actin-based lamella formation in Drosophila S2 cells. J. Cell Biol. 162, 1079–1088 (2003).

  19. 19.

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

  20. 20.

    , , & ADF/cofilin controls cell polarity during fibroblast migration. Curr. Biol. 13, 252–257 (2003).

  21. 21.

    , , , & 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).

  22. 22.

    , , , & A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J. Exp. Med. 184, 1101–1109 (1996).

  23. 23.

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

  24. 24.

    , , , & Aip1p interacts with cofilin to disassemble actin filaments. J. Cell Biol. 145, 1251–1264 (1999).

  25. 25.

    , & Physiological and pathological roles of Apaf1 and the apoptosome. J. Cell. Mol. Med. 7, 21–34 (2003).

  26. 26.

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

  27. 27.

    , , & 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).

  28. 28.

    , , & Rapid actin monomer-insensitive depolymerization of Listeria actin comet tails by cofilin, coronin, and Aip1. J. Cell Biol. 175, 315–324 (2006).

Download references

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.).

Author information

Author notes

    • Shin Jung Kang

    Current address: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.

Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.

    • Juying Li
    • , Shin Jung Kang
    • , Hong Zhu
    •  & Junying Yuan
  2. Department of Systems Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.

    • William M. Brieher
    •  & Timothy Mitchison
  3. The CBR Institute for Biomedical Research, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.

    • M. Lucila Scimone
    •  & Ulrich H. von Andrian
  4. Department of Physiology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

    • Helen Yin

Authors

  1. Search for Juying Li in:

  2. Search for William M. Brieher in:

  3. Search for M. Lucila Scimone in:

  4. Search for Shin Jung Kang in:

  5. Search for Hong Zhu in:

  6. Search for Helen Yin in:

  7. Search for Ulrich H. von Andrian in:

  8. Search for Timothy Mitchison in:

  9. Search for Junying Yuan in:

Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Junying Yuan.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    Supplementary Figures S1, S2, S3, S4 and Supplementary Methods

Videos

  1. 1.

    Supplementary Information

    Supplementary Movie S1

  2. 2.

    Supplementary Information

    Supplementary Movie S2

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ncb1541

Further reading