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
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / metabolism
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Caspases / genetics
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Caspases / metabolism*
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Caspases, Initiator
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Cell Line, Tumor
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Cell Movement / physiology*
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Chemokine CXCL12
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Chemokines, CXC / pharmacology
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Cofilin 1 / genetics
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Cofilin 1 / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Lipopolysaccharides / pharmacology
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Lymphocytes / cytology
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Lymphocytes / drug effects
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Lymphocytes / metabolism
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Macrophages, Peritoneal / cytology
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Models, Biological
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Mutation
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N-Formylmethionine Leucyl-Phenylalanine / pharmacology
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Protein Binding
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RNA Interference
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Transfection
Substances
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Actins
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Amino Acid Chloromethyl Ketones
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Cfl1 protein, mouse
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Chemokine CXCL12
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Chemokines, CXC
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Cofilin 1
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Cxcl12 protein, mouse
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Cysteine Proteinase Inhibitors
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Lipopolysaccharides
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Microfilament Proteins
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actin interacting protein 1
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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N-Formylmethionine Leucyl-Phenylalanine
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Casp4 protein, mouse
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Caspases
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Caspases, Initiator