Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
- Stanford University School of Medicine, United States
- The Francis Crick Institute, United Kingdom
- University of Oxford, United Kingdom
- Washington University School of Medicine, United States
Abstract
Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike most GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.
Article and author information
Author details
Funding
National Institutes of Health (GM106078, HL067773)
- Douglas F Covey
- Rajat Rohatgi
Cancer Research UK (C20724/A14414)
- Christian Siebold
Taylor Family institute for Psychiatric Research
- Douglas F Covey
Ford Foundation
- Giovanni Luchetti
National Science Foundation
- Sigrid Nachtergaele
Nuffield Department of Medicine, Oxford University
- Eamon FX Byrne
EMBO LTF (1438-2013)
- Andreas Sagner
HFSP LTF (LT000401/2014-L)
- Andreas Sagner
People Programme of the EU's Seventh Framework Programme (FP7-2013)
- Andreas Sagner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Luchetti et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
eLife 5:e20304.
https://doi.org/10.7554/eLife.20304
Further reading
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- Biochemistry and Chemical Biology
- Developmental Biology
Cholesterol can regulate the Hedgehog signalling pathway by directly binding to a receptor on the cell surface.
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- Biochemistry and Chemical Biology
The biosynthesis of cyclic 3′,5′-adenosine monophosphate (cAMP) by mammalian membrane-bound adenylyl cyclases (mACs) is predominantly regulated by G-protein-coupled receptors (GPCRs). Up to now the two hexahelical transmembrane domains of mACs were considered to fix the enzyme to membranes. Here, we show that the transmembrane domains serve in addition as signal receptors and transmitters of lipid signals that control Gsα-stimulated mAC activities. We identify aliphatic fatty acids and anandamide as receptor ligands of mAC isoforms 1–7 and 9. The ligands enhance (mAC isoforms 2, 3, 7, and 9) or attenuate (isoforms 1, 4, 5, and 6) Gsα-stimulated mAC activities in vitro and in vivo. Substitution of the stimulatory membrane receptor of mAC3 by the inhibitory receptor of mAC5 results in a ligand inhibited mAC5–mAC3 chimera. Thus, we discovered a new class of membrane receptors in which two signaling modalities are at a crossing, direct tonic lipid and indirect phasic GPCR–Gsα signaling regulating the biosynthesis of cAMP.
