Cholesterol access in cellular membranes controls Hedgehog signaling

Abstract

The Hedgehog (Hh) signaling pathway coordinates cell–cell communication in development and regeneration. Defects in this pathway underlie diseases ranging from birth defects to cancer. Hh signals are transmitted across the plasma membrane by two proteins, Patched 1 (PTCH1) and Smoothened (SMO). PTCH1, a transporter-like tumor-suppressor protein, binds to Hh ligands, but SMO, a G-protein-coupled-receptor family oncoprotein, transmits the Hh signal across the membrane. Recent structural, biochemical and cell-biological studies have converged at the surprising model that a specific pool of plasma membrane cholesterol, termed accessible cholesterol, functions as a second messenger that conveys the signal between PTCH1 and SMO. Beyond solving a central puzzle in Hh signaling, these studies are revealing new principles in membrane biology: how proteins respond to and remodel cholesterol accessibility in membranes and how the cholesterol composition of organelle membranes is used to regulate protein function.

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Fig. 1: Hedgehog signal transmission across the plasma membrane.
Fig. 2: Multiple sterol binding sites in SMO.
Fig. 3: Structural similarities between PTCH1 and the cholesterol transporter NPC1.
Fig. 4: Cholesterol accessibility in cellular membranes.
Fig. 5: Changes in accessible cholesterol influence Hh signaling in target cells.
Fig. 6: Hh signal transmission by ligand-controlled changes in cholesterol accessibility of the ciliary membrane.
Fig. 7: Two models for the regulation of SMO by PTCH1 at primary cilia.

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Acknowledgements

We acknowledge G. Pusapati for help with the figures and comments on the manuscript. C.S. was supported by grants from Cancer Research UK (C20724/A26752) and the European Research Council (647278), R.R. by grants from the National Institutes of Health (GM118082 and GM106078), and A.R. by grants from the NIH (HL20948), Welch Foundation (I-1793) and Leducq Foundation (19CVD04).

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Radhakrishnan, A., Rohatgi, R. & Siebold, C. Cholesterol access in cellular membranes controls Hedgehog signaling. Nat Chem Biol 16, 1303–1313 (2020). https://doi.org/10.1038/s41589-020-00678-2

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