Caspases and Their Regulators Beyond Apoptosis

Abstract

Geisbrecht and Montell report an unexpected role for Drosophila inhibitor of apoptosis 1 (DIAP1), a caspase inhibitor, in the promotion of cell migration. Thread , the gene encoding DIAP1, was identified in a screen for genes that rescued border cell migration in Drosophila with a dominant-negative Rac (RacN17). Overexpression of DIAP1 rescued epithelial cell migration defects caused by RacN17, but not by constitutively active Rac mutants, and DIAP1 did not rescue myoblast fusion defects caused by RacN17. Thus, DIAP1 appears to be involved in a subset of Rac-mediated migration processes. Analysis of egg chambers of th mutants indicated various defects, none of which appeared related to increased apoptosis, which would have been predicted based on DIAP1 antiapoptotic action. These defects included migration defects. Flies that had DIAP1-containing mutations in the BIR domains, which are also required for antiapoptotic activity, caused egg chamber cell migration defects. Although the migration effects appeared independent from antiapoptotic activity of DIAP1, the activity of a caspase target of DIAP1 did appear to be involved in migration. Dominant-negative forms of Dronc, which corresponds to caspase-9 in mammals, or loss-of-function mutants in the Dronc activator Dark, which is the homolog to mammalian Apaf-1, also rescued the RacN17-induced border cell migration defects. The effects of Rac and DIAP1 may be mediated through effects on the actin cytoskeleton, because filamentous actin (F-actin) was reduced in th mutant cells and actin5C rescues RacN17 migration defects. Overexpression of profilin, which maintains the pool of adenosine triphosphate (ATP)-bound actin, also rescued border cell migration defects caused by RacN17. Profilin and DIAP1 both interacted with Rac in a nucleotide-independent manner. Thus, caspases and their regulators appear to have a role beyond apoptosis in controlling some cell migration processes, possibly mediated through effects on the cytoskeleton. E. R. Geisbrecht, D. J. Montell, A role for Drosophila IAP1-mediated caspase inhibition in Rac-dependent cell migration. Cell 118 , 111-125 (2004). [Online Journal]