Death-associated protein kinase 3 (DAPK3) contributes to intestinal epithelial wound healing and the resolution of experimental colitis in mice

Abstract

Various signaling molecules affecting epithelial restitution and wound healing are dysregulated in ulcerative colitis. Recent evidence demonstrates the necessity of Hippo-YAP/TAZ signaling, interceded by cytoskeletal remodeling, for intestinal regeneration. Death-associated protein kinase 3 (DAPK3) is a regulator of actin cytoskeleton reorganization that controls proliferation and apoptosis. Pharmacological inhibition of DAPK3 in Caco-2 human intestinal epithelial cells (IECs) with the HS38 compound augmented cell proliferation and enhanced wound closure. This phenotype corresponded with the increased colocalization of Yes-associated protein (YAP) with F-actin, which is indicative of YAP activation. The administration of HS38 impeded the resolution of intestinal injury and attenuated epithelial-specific proliferation after acute colitis induced by dextran-sodium-sulphate (DSS) in mice. During recovery from DSS-induced colitis, IEC proliferation was repressed, and mice exhibited increased disease severity when HS38 was applied to inhibit DAPK3. Moreover, HS38 treatment increased YAP nuclear localization in IECs, an indicator of signal activation. In summary, this study established DAPK3 as a key factor in intestinal epithelial regeneration and colitis progression by way of YAP signaling. Nevertheless, the role that DAPK3 play in different cell types will need further investigation to decipher the full consequence of DAPK3 inhibition on epithelial homeostasis.