Sufu recruits GSK3β for efficient processing of Gli3

Hedgehog (Hh) signaling activates the transcription factor Gli by suppressing the function of the suppressor of fused (Sufu) protein in mammals. Here, a novel role of mammalian Sufu is identified where it mediates the phosphorylation of Gli3 by GSK3β, essential for Gli3 processing to generate a transcriptional repressor for Hh-target genes. Studies using Sufu(−/−) mouse embryonic fibroblasts and siRNA targeting Sufu demonstrate the requirement of Sufu for Gli3 processing. In addition, Sufu can bind to GSK3β as well as Gli3, and mediates formation of the trimolecular complex Gli3/Sufu/GSK3β. Thus, Sufu stimulates Gli3 phosphorylation by GSK3β and Gli3 processing. Furthermore, Sonic Hh stimulation dissociates the Sufu/GSK3β complex from Gli3, resulting in the blockade of Gli3 processing. Collectively, Sufu presumably functions as a GSK3β recruiter for Hh-dependent regulation of Gli3 processing. Such a function is very similar to that of Costal2 in Drosophila, suggesting a functional complementation through evolution.