Caspase for Cell Movement

Abstract

Caspases are well known for their roles in programmed cell death and for their roles in maturation of inflammatory cytokines. Li et al . now show that caspase 11 also has a role in regulating actin dynamics that contributes to cell migration. Leukocytes deficient for caspase 11 were defective in cell migration in culture (transwell assays) and in vivo. When injected into host mice, these cells were defective in homing (leaving the blood and reaching the target organs). Affinity purification experiments identified actin interacting protein 1 (AIP1) as a binding partner for caspase 11. Coimmunoprecipitation experiments with various truncation mutants of AIP1 and caspase 11 showed that the CARD domain of caspase 11 and the C-terminal WD propeller domain of AIP1 were required for the interaction. Notably, the protease domain of caspase 11 was not required. RNA interference experiments confirmed that AIP1 was important for cell migration with membrane ruffling defective in the absence of AIP1 (ruffling was also defective in the caspase 11-deficient cells). Overexpression of a catalytically inactive caspase 11 restored migration to the AIP knockdown cells. In vitro actin polymerization assays showed that caspase 11 synergized with AIP1 to stimulate cofilin-mediated actin depolymerization, whereas caspase 11 in the absence of AIP1 did not affect cofilin-mediated actin depolymerization. In an actin pelleting assay, the addition of caspase 11 with cofilin and AIP1 increased the soluble actin, consistent with enhanced depolymerization. This did not require protease activity, as it was not inhibited by the addition of a pan-caspase inhibitor. The action of caspase 11 did require the presence of AIP1. In the presence of actin alone, caspase 11 was shifted to the pellet, suggesting an interaction with the actin filament; in the presence of cofilin and AIP1, caspase 11 shifted to the supernatant, suggesting an interaction with the actin monomers as well. Thus, caspase 11 now appears to influence multiple inflammatory cell processes: cytokine secretion, apoptosis, and cell migration. The authors propose that caspase 11 may serve early in the inflammatory response by aiding the delivery of cytokine-producing cells to the site of infection and then by terminating cytokine production through stimulation of apoptosis. Bailly discusses the mechanisms of regulation of cofilin in an associated commentary. J. Li, W. M. Brieher, M. L. Scimone, S. J. Kang, H. Zhu, H. Yin, U. H. von Andrian, T. Mitchison, J. Yuan, Caspase-11 regulates cell migration by promoting Aip1-cofilin-mediated actin depolymerization. Nat. Cell Biol. 9 , 276-286 (2007). [PubMed] M. Bailly, Moving away from death: When caspase-11 meets cofilin. Nat. Cell Biol. 9 , 245-246 (2007). [PubMed]