Abstract
Previously we proposed that transmission of the hedgehog signal across the plasma membrane by Smoothened is triggered by its interaction with cholesterol (Luchetti et al., 2016). But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find that Smoothened activation and Hedgehog signaling are driven by a biochemically-defined, small fraction of membrane cholesterol, termed accessible cholesterol. Increasing cholesterol accessibility by depletion of sphingomyelin, which sequesters cholesterol in complexes, amplifies Hedgehog signaling. Hedgehog ligands increase cholesterol accessibility in the membrane of the primary cilium by inactivating the transporter-like protein Patched 1. Trapping this accessible cholesterol blocks Hedgehog signal transmission across the membrane. Our work shows that the organization of cholesterol in the ciliary membrane can be modified by extracellular ligands to control the activity of cilia-localized signaling proteins.
Highlights
A long-standing mystery in hedgehog (HH) signaling is how Patched 1 (PTCH1), the receptor for HH ligands, inhibits Smoothened (SMO), a G-protein-coupled receptor (GPCR) family protein that transduces the HH signal across the membrane (Kong et al, 2019)
Two features explain how a seemingly abundant membrane lipid like cholesterol can play an instructive role as a second messenger in a signaling pathway
This thermodynamically distinct pool of accessible cholesterol with high chemical activity ranges from ~2% of total plasma membrane cholesterol in lipid depleted cells to ~15% of total plasma membrane cholesterol in lipid replete cells (Das et al, 2014)
Summary
A long-standing mystery in hedgehog (HH) signaling is how Patched 1 (PTCH1), the receptor for HH ligands, inhibits Smoothened (SMO), a G-protein-coupled receptor (GPCR) family protein that transduces the HH signal across the membrane (Kong et al, 2019). We and others demonstrated that cholesterol directly binds and activates SMO and proposed that PTCH1 regulates SMO by restricting its access to cholesterol (Byrne et al, 2016; Huang et al, 2016; Luchetti et al, 2016). Biochemical studies show that PTCH1 can bind and efflux sterols from cells (Bidet et al, 2011), and structural studies highlight the homology of PTCH1 to the cholesterol transporter Niemann-Pick C1 (NPC1) (Gong et al, 2018; Kong et al, 2019; Kowatsch et al, 2019; Qian et al, 2019; Qi et al, 2019a; Qi et al, 2018a; Qi et al, 2018b; Zhang et al, 2018). The resolution of the PTCH1 cryoEM structures is not high enough to distinguish cholesterol from other sterol lipids as PTCH1
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