Uracil-induced signaling pathways for DUOX-dependent gut immunity

Abstract

Intestinal dual oxidase (DUOX) activation is the first line of host defense against enteric infection in Drosophila. DUOX enzymatic activity is mainly controlled by phospholipase C-β (PLCβ)-dependent calcium mobilization, whereas DUOX gene expression is mainly controlled by the MEKK1-p38 mitogen-activated protein kinase pathway. Furthermore, bacterial-derived uracil molecules act as ligands for DUOX activation. However, our current understanding of uracil-induced signal transduction pathways remain incomplete. We have recently found that uracil stimulates Hedgehog signaling, which in turn upregulates cadherin99C (Cad99C) expression in enterocytes. Cad99C molecules, along with PLCβ and protein kinase C, induce the formation of signaling endosomes that facilitate intracellular calcium mobilization for DUOX activity. These observations illustrate the complexity of signaling cascades in uracil-induced signaling pathways. Here, we further demonstrated the role of lipid raft formation and calmodulin-dependent protein kinase-II on endosome formation and calcium mobilization, respectively. Moreover, we will provide a brief discussion on two different models for uracil recognition and uracil-induced DUOX activation in Drosophila enterocytes.

The Plasma Membrane: A Platform for Intra- and Intercellular Redox Signaling

“…However, phospholipase C β (PLCβ) and protein kinase Cα (PKCα), two factors inducing Ca 2+ -mediated activation of DUOXes, are enriched in lipid rafts [ 142 , 143 ], a fact that would predict DUOXes localization to the same site. In support of this hypothesis, a recent publication has linked LR-dependent Ca 2+ signaling to DUOX-mediated ROS generation in Drosophila during pathogenic infection [ 144 ].…”

Mini review: immunologic functions of dual oxidases in mucosal systems of vertebrates

“…In this pathway, a kind of calcium-dependent cell adhesion molecule, Cadherin 99C, expression levels increase can induce Ca 2+ mobilization together with phospholipase Cβ and protein kinase C. The high Ca 2+ concentration in the cytoplasm initiates DUOX enzymatic activity (Lee et al, 2015a). Additionally, the induction of lipid raft formation, lipolysis, and CaMKII can promote DUOX enzymatic activity (Lee et al, 2018(Lee et al, , 2015b. DUOX-mediated ROS production requires the formation of a DUOX complex rather than an individual DUOX molecule.…”

The Hedgehog Signaling Pathway Emerges as a Pathogenic Target

“…The Hh pathway also has postnatal roles in defining the immune response which is conserved from flies to humans, although the relevant signaling output and how it is applied as a defense mechanism differs between vertebrates and invertebrates. In a study conducted in Drosophila by Lee et al, Hedgehog signaling was found to be required as a first line of defense against harmful uracil-secreting pathogens in the gut by triggering the production of microbicidal reactive oxygen species (ROS) [ 60 , 95 , 96 ]. Flies expressing RNAis directed to several canonical Hh pathway components showed reduced ROS production upon bacterial infection and a consequent higher mortality rate.…”