title: Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization.
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.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Juying
authors.initials: J
authors.lastname: Li
authors.forename: William M
authors.initials: WM
authors.lastname: Brieher
authors.forename: M Lucila
authors.initials: ML
authors.lastname: Scimone
authors.forename: Shin Jung
authors.initials: SJ
authors.lastname: Kang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.forename: Helen
authors.initials: H
authors.lastname: Yin
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Timothy
authors.initials: T
authors.lastname: Mitchison
authors.forename: Junying
authors.initials: J
authors.lastname: Yuan
mesh_terms: D000199:Actins / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D014162:Transfection
chemical_list: D000199:Actins; D000590:Amino Acid Chloromethyl Ketones; C495811:Cfl1 protein, mouse; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D051338:Cofilin 1; C515256:Cxcl12 protein, mouse; D015853:Cysteine Proteinase Inhibitors; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; C115237:actin interacting protein 1; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D009240:N-Formylmethionine Leucyl-Phenylalanine; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator