Tukachinsky et al. reveal how Hedgehog (Hh) signaling in the primary cilium activates the Gli family of transcription factors.
In vertebrates, the Hh pathway begins in the primary cilium, where the Hh ligand binds its receptor Patched, leading to the activation and recruitment of the membrane protein Smoothened (Smo). Pathway activation culminates in the movement of Gli transcription factors into the nucleus. In unstimulated cells, Glis are kept inactive in the cytoplasm by the protein Suppressor of Fused (SuFu), but how Hh and Smo switch on the transcription factors is unknown.
Tukachinsky et al. found that Hh induced the rapid accumulation of both SuFu and Gli in primary cilia, and that this required Smo's activation. Hh also disrupted the interaction between SuFu and Gli. Protein kinase A, an inhibitor of Hh signaling that acts downstream of Smo, blocked SuFu and Gli's ciliary recruitment and preserved their association, suggesting that active Smo normally brings the proteins to cilia to liberate Gli molecules and permit their translocation to the nucleus.
Senior author Adrian Salic now wants to investigate whether Smo acts directly or indirectly on SuFu–Gli complexes and how activated Gli proteins subsequently move from cilia to nuclei—preliminary results indicate that this latter step could involve microtubules. Salic also wants to use quantitative live imaging to follow the ciliary recruitment of SuFu and Gli in greater detail.