Figure 1.

Schematic illustration of Hh signaling and how pathogens may modify pathway activity. (A) In the absence of Hh ligand, the receptor Ptch inhibits Smo activation. Ci/Gli is retained in the cytoplasm tethered to microtubules (in flies) or primary cilia (in mammals) through a complex of several proteins, simplistically termed here as “transcription factor inhibitory complex” (TFIC). This complex promotes Ci/Gli phosphorylation, which results in partial proteolysis to a repressor form that can readily enter the nucleus and repress expression of some Gli targets. (B) When Hh ligand binds to Ptch, inhibition upon Smo is relieved and the C-terminus of Smo is phosphorylated which promotes the release of Ci/Gli from the TFIC. The activated form of Gli/Ci can enter the nucleus and activate expression of Hh targets. Examples of canonical Gli target genes as well as those involved specifically in proliferation, immunity, and migration are given. Helicobacter Pylori (H.p.) has been proposed to act, in part, by repressing expression of the Hh ligand. Influenza NS1 and HBV X protein have been proposed to interact directly with Gli/Ci, but the precise mechanism by which they affect transcriptional activity has not been fully elucidated. The diagram also shows the pathway components which can be inhibited by FDA-approved small molecules: Vidmodegib and Sonidegib inhibit the activity of Smo, whereas arsenic trioxide (ATO) inhibits the activity of Gli1/2.