IKK and Caspases in Regulating Cell Shape

Abstract

Two reports this week provide evidence that in Drosophila IKKε, a kinase of the IKK family, which stands for inhibitor of nuclear factor κB (NF-κB) kinase, promotes the degradation of DIAP1, the Drosophila inhibitor of apoptosis protein, and activates the DRONC caspase to regulate nonapoptotic processes. Kuranaga et al. found mutant forms of IKKε lacking kinase activity in a screen for suppressors of cell death. Although overexpression of IKKε did promote cell death, knockdown of IKKε did not suppress cell death, suggesting that the IKKε may have a nonapoptotic function. IKKε promoted the phosphorylation of DIAP1 and the degradation of DIAP1 in S2 cells. Although the two proteins coimmunoprecipitated from S2 cells, purified proteins did not physically interact, suggesting that the interaction may be indirect. In wing discs, mild caspase activation was detected in the absence of apoptosis, and this caspase activation was inhibited when IKKε was knocked down. Oshima et al. showed that overexpression of IKKε disrupted epithelial integrity in the Drosophila embryo tracheal system, and this was associated with a loss of apical F actin and loss of cell polarity in the epithelial cells. In S2 cells, altering the abundance of IKKε altered cell morphology, with decreased IKKε stimulating the frequency of serrate- or stellate-shaped cells and decreasing retrograde F actin flow and increased IKKε stimulating membrane ruffling and increasing retrograde F actin flow. In the trachea, sensory bristles, and antenna arista, inhibition of IKKε promoted excessive branching of the structures, which was consistent with disruption in actin regulation. Genetic interactions were observed in the arista phenotype between IKKε, DIAP1, and DRONC, suggesting that IKKε regulates the F actin cytoskeleton by stimulating caspase activity. Thus, these two results uncover a novel activation of caspases through an IKK and a nonapoptotic function for caspases in regulating the actin cytoskeleton. (Bergmann and Montell discuss the implications of these findings.) E. Kuranaga, H. Kanuka, A. Tonoki, K. Takemoto, T. Tomioka, M. Kobayashi, S. Hayashi, M. Miura, Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. Cell 126 , 583-596 (2006). [PubMed] K. Oshima, M. Takeda, E. Kuranaga, R. Ueda, T. Aigaki, M. Miura, S. Hayashi, IKKε regulates F actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis. Curr. Biol. 16 , 1531-1537 (2006). [PubMed] A. Bergmann, IKKε signaling: Not just NF-κB. Curr. Biol. 16 , R588-R590 (2006). [PubMed] D. J. Montell, A kinase gets caspases into shape. Cell 126 , 450-452 (2006). [PubMed]