A Reaction-Diffusion Network model predicts a dual role of Cactus/IκB to regulate Dorsal/NFκB nuclear translocation in Drosophila

Dorsal-ventral patterning of the Drosophila embryo depends on the NF{kappa}B superfamily transcription factor Dorsal (Dl). Toll receptor activation signals for degradation of the I{kappa}B inhibitor Cactus (Cact), leading to a ventral-to-dorsal nuclear Dl gradient. Cact is critical for Dl nuclear import, as it binds to and prevents Dl from entering the nuclei. Quantitative analysis of cact mutants revealed an additional Cact function to promote Dl nuclear translocation in ventral regions of the embryo. To investigate this dual Cact role, we developed a predictive model based on a reaction-diffusion regulatory network. This network considers non-uniform Toll activation as well as Toll-dependent Dl nuclear import and Cact degradation. In addition, it incorporates translational control of Cact levels by Dl, a Toll-independent pathway for Cact regulation and reversible nuclear-cytoplasmic Dl flow. Our model successfully reproduces wild-type data and emulates the Dl nuclear gradient in mutant dl and cact allelic combinations. Our results indicate that the dual role of Cact depends on targeting distinct Dl complexes along the dorsal-ventral axis: In the absence of Toll activation, free Dl-Cact trimers inhibit direct Dl nuclear entry; upon ventral-lateral Toll activation, Dl-Cact trimers are recruited into predominant signaling complexes and promote active Dl nuclear translocation. Simulations suggest that Toll-independent regulatory mechanisms that target Cact are fundamental to reproduce the full assortment of Cact effects. Considering the high evolutionary conservation of these pathways, our analysis should contribute to understand NF{kappa}B/c-Rel activation in other contexts such as in the vertebrate immune system and disease.