The Hedgehog Signaling Pathway Emerges as a Pathogenic Target

Abstract

The Hedgehog (Hh) signaling pathway plays an essential role in the growth, development, and homeostatis of many tissues in vertebrates and invertebrates. Much of what is known about Hh signaling is in the context of embryonic development and tumor formation. However, a growing body of evidence is emerging indicating that Hh signaling is also involved in postnatal processes such as tissue repair and adult immune responses. To that extent, Hh signaling has also been shown to be a target for some pathogens that presumably utilize the pathway to control the local infected environment. In this review, we discuss what is currently known regarding pathogenic interactions with Hh signaling and speculate on the reasons for this pathway being a target. We also hope to shed light on the possibility of using small molecule modulators of Hh signaling as effective therapies for a wider range of human diseases beyond their current use in a limited number of cancers.

Keywords: Epstein Barr virus; Gli; H. pylori; HIV; Hedgehog; Hepatitis B and C; fibrosis; immunity; influenza.

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.

Figure 2

Influenza NS1 increases Hh target gene expression in Drosophila and mice. (A) Schematic diagram of a Drosophila wing imaginal disc with the anterior/posterior (A/P) border, the domain where Hh signaling is active, demarcated in red. The dashed box represents the area of the disc that was imaged in B. (B) Influenza NS1, expressed from a transgene in the wing imaginal disc, increases expression of the Hh target gene reporter, dpp-lacZ, at the A/P border compared with a disc with no transgene (no tg). (C,D) Infected mouse lungs show a cell-autonomous increase in expression of the Hh targets, BMP2 (C) and Ptch1 (D) compared with uninfected lungs. Target proteins are in green, NS1 is in red.

Figure 3

Hypothesis for what occurs during a pathogenic interaction with Hh signaling. Pathogens that cause damage to the host tissue promote activation of Hh signaling due to the key roles it plays in repair processes and immunity (green boxes). If not regulated properly, these cellular processes can cause fibrosis and an imbalanced immune response, respectively (red boxes). Pathogens, such as Influenza, EBV, HBC, HCV, HIV, and H.p., have been shown to directly modulate pathway activity once signaling is activated and may do so in order to exacerbate or restrain these detrimental outcomes.