Zinc Inhibits Hedgehog Autoprocessing: Linking Zinc Deficiency with Hedgehog Activation

Zinc is an essential metal with wide-ranging biological functions while Hedgehog (Hh) signaling plays crucial roles in both development and disease. Here we describe a mechanistic interaction between zinc and Hh signaling. Hh ligand, the upstream activator of Hh signaling, originates from Hh autoprocessing, in which Hh precursor protein undergoes self-cleavage and cholesterol modification. In vitro assay showed zinc inhibits Hh autoprocessing with IC50 of 2 μM. Solution NMR revealed that zinc interacts with active site residues of Hh autoprocessing domain while ITC indicated that the binding is driven mostly by enthalpy with 1:1 stoichiometry. We further demonstrated zinc inhibition of Hh autoprocessing extends to a cellular environment through cell culture studies. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer and autism. Our data suggest a novel, causal relationship between zinc deficiency and the overproduction of Hh ligand: zinc deficiency likely enhances Hh autoprocessing and the production of Hh ligand, thereby activating Hh signaling in diseases.