Endogenous Cholesterol Induces Smoothened to Drive Hedgehog Signaling

The Hedgehog signaling pathway is a developmental pathway that is activated when Hedgehog ligands bind to the Patched (PTCH) receptor, subsequently relieving PTCH-mediated repression of the transmembrance oncoprotein Smoothened (SMO). PTCH1 contains a sterol-sensing domain that is critical for inhibiting SMO and has homology to bacterial transporters of small lipophilic molecules. Because oxysterols, which are oxidized cholesterol derivatives, have been shown to activate SMO, it has been proposed that PTCH removes oxysterols from SMO to suppress SMO activity. However, endogenous oxysterols are present at low levels that are insufficient to activate Hedgehog signaling, while also activating SMO in a PTCH-independent manner. Huang and colleagues sought to identify the cellular sterol that mediates SMO activation and define the mechanism underlying its interaction with and activation of SMO. Crystallization of the extracellular cysteine-rich domain of SMO (SMOCRD), alone or in complex with oxysterol, identified an oxysterol-induced conformational change, which was sufficient for SMO activation, suggesting that sterol binding is integral for Hedgehog signaling. Cholesterol, which is the most abundant sterol present in cells, was shown to bind SMOCRD and to activate Hedgehog signaling in a dose-dependent manner. Further, cholesterol, but not an oxysterol, syngergized with sonic hedgehog (SHH) to activate Hedgehog signaling. Consistent with these findings, SMO mutants defective in binding and responding to oxysterols were still responsive to cholesterol and to SHH. Taken together, these findings describe a sterol–SMOCRD interaction–dependent mechanism underlying SMO activation, and identify cholesterol as the sterol critical for SMO activation by PTCH-mediated Hedgehog signaling.

Huang P, Nedelcu D, Watanabe M, Jao C, Kim Y, Liu J, et al. Cellular cholesterol directly activates smoothened in hedgehog signaling. Cell 2016;166:1176–87.e14.

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