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.

1. Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
2. Department of Systems Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
3. The CBR Institute for Biomedical Research, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
4. Department of Physiology, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
5. Current address: Department of Molecular Biology, Sejong University, Seoul 143-747, Korea.

Correspondence to: Junying Yuan¹ e-mail: jyuan@hms.harvard.edu

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