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

Nat Cell Biol. 2007 Mar;9(3):276-86. doi: 10.1038/ncb1541. Epub 2007 Feb 11.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Caspases / genetics
  • Caspases / metabolism*
  • Caspases, Initiator
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Chemokine CXCL12
  • Chemokines, CXC / pharmacology
  • Cofilin 1 / genetics
  • Cofilin 1 / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Lipopolysaccharides / pharmacology
  • Lymphocytes / cytology
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages, Peritoneal / cytology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism*
  • Models, Biological
  • Mutation
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Protein Binding
  • RNA Interference
  • Transfection

Substances

  • Actins
  • Amino Acid Chloromethyl Ketones
  • Cfl1 protein, mouse
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cofilin 1
  • Cxcl12 protein, mouse
  • Cysteine Proteinase Inhibitors
  • Lipopolysaccharides
  • Microfilament Proteins
  • actin interacting protein 1
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • N-Formylmethionine Leucyl-Phenylalanine
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator