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 intestinal absorption of essential nutrients, especially those not readily biosynthesized, is a critical physiological process for maintaining homeostasis. Numerous studies have indicated that intestinal absorption is mediated by various membrane transporters. Citrate, a crucial bioactive compound produced as an intermediate in the Krebs cycle, is absorbed in the small intestine through carrier-mediated systems because of its high hydrophilicity. While the luminal absorption of citrate is mediated by Na+-dicarboxylate cotransporter 1 (NaDC1/SLC13A2), the mechanism governing the release of the transported citrate into the bloodstream remains unknown. Here, we explored the transporters responsible for intestinal citrate absorption at the basolateral membrane, focusing on highly expressed orphan transporters in the small intestine as candidates. Consequently, SLC35G1, originally identified as a partner of stromal interaction molecule 1, a cell surface transmembrane glycoprotein, was found to play a role in the intestinal absorption of citrate at the basolateral membrane. Furthermore, our results revealed that SLC35G1-mediated citrate transport was diminished by chloride ions at physiologically relevant extracellular concentrations. This suggests that SLC35G1, to our best knowledge, is the first transporter identified to be extremely sensitive to chloride ions among those functioning on the basolateral membrane of intestinal epithelial cells. This study provides valuable insights into the intestinal absorption of citrate and significantly contributes to elucidating the poorly understood molecular basis of the intestinal absorption system.
