Suppressor of Fused Chaperones Gli Proteins To Generate Transcriptional Responses to Sonic Hedgehog Signaling

Abstract

Cellular responses to the graded Sonic Hedgehog (Shh) morphogenic signal are orchestrated by three Gli genes that give rise to both transcription activators and repressors. An essential downstream regulator of the pathway, encoded by the tumor suppressor gene Suppressor of fused (Sufu), plays critical roles in the production, trafficking, and function of Gli proteins, but the mechanism remains controversial. Here, we show that Sufu is upregulated in active Shh responding tissues and accompanies Gli activators translocating into and Gli repressors out of the nucleus. Trafficking of Sufu to the primary cilium, potentiated by Gli activators but not repressors, was found to be coupled to its nuclear import. We have identified a nuclear export signal (NES) motif of Sufu in juxtaposition to the protein kinase A (PKA) and glycogen synthase kinase 3 (GSK3) dual phosphorylation sites and show that Sufu binds the chromatin with both Gli1 and Gli3. Close comparison of neural tube development among individual Ptch1 Ϫ/Ϫ , Sufu Ϫ/Ϫ , and Ptch1 Ϫ/Ϫ ; Sufu Ϫ/Ϫ double mutant embryos indicates that Sufu is critical for the maximal activation of Shh signaling essential to the specification of the most-ventral neurons. These data define Sufu as a novel class of molecular chaperone required for every aspect of Gli regulation and function.

Molecular mechanisms of suppressor of fused in regulating the hedgehog signalling pathway (Review)

“…Following Smo activation, the cytoplasmic complex containing Sufu and GLI2/3 is recruited to the primary cilium tip, where dissociation of the complex releases full-length GLI2 and GLI3 (72), which are subsequently translocated into the nucleus as potential transcriptional activators to take the place of GLIR, while Sufu is induced to degrade (73,74). Recently, it was reported that responding to Hh signalling, Sufu accompanies GLI1 to the primary cilium, which is coupled to the subsequent nuclear transport of GLI1 (75). The necessity of the primary cilium for GLI derepression is supported by the report of a novel central domain characterized in GLI2 that is essential for both primary cilium localization and transcriptional activity (76).…”

“…Notably, the stabilities of the GLI2R, GLI3R and GLI1 proteins are not influenced in this manner. Nevertheless, a recent study reported that Sufu is also essential for maintaining high protein level and nuclear accumulation of GLI1 in response to Hh signalling, sustaining the proliferation of granule neuron precursor cells (75). Mechanistically, Sufu-mediated stabilization of full-length GLI2/3 is of great importance.…”

“…For instance, it can recruit the SAP18-mSin3-HDAC co-repressor complex to suppress GLI transcriptional activity (86,87). SAP18 is recruited to GLI3R-Sufu to form a suppressive complex occupying the GLI binding site when Hh signalling is quiescent, and upon Hh pathway activation this suppressive complex will be replaced by GLI1-Sufu (75) to activate the transcription of target genes. Other nuclear proteins mainly involved in basal transcription machinery were identified to interact with Sufu in a yeast two-hybrid screen using mouse Sufu as a bait, indicating crucial functions of Sufu in the nucleus.…”

SHH Signaling Pathway Drives Pediatric Bone Sarcoma Progression

“…Suppressor of fused homolog (Sufu) is a crucial inhibitor of the SHH cascade [28]. Indeed, Sufu sequesters glioma-associated oncogene homolog (Gli) in the cytosol [29]. The mammalian Gli gene family comprises three isoforms: Gli1, Gli2 and Gli3 (Figure 1).…”

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

“…This raised the possibility that the stabilization of GLIS3 by SUFU may be due to its inhibition of GLIS3 interaction with CUL3. SUFU plays also an important role in the control of hedgehog/GLI signaling and regulates this pathway at multiple levels [40, 41]. In the case of GLIS3, co-expression of GLIS3 and SUFU causes translocation of SUFU to the nucleus suggesting that GLIS3 and SUFU are part of a nuclear protein complex.…”