Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation

The G protein-coupled receptor Smoothened (Smo) is the signal transducer of the Sonic Hedgehog (Shh) pathway. Smo signals through G protein-dependent and -independent routes, with G protein-independent canonical signaling to Gli effectors requiring Smo accumulation in the primary cilium. The mechani...

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Published in:	Cell reports (Cambridge) Vol. 19; no. 10; pp. 2074 - 2087
Main Authors:	Arensdorf, Angela M., Dillard, Miriam E., Menke, Jacob M., Frank, Matthew W., Rock, Charles O., Ogden, Stacey K.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 06-06-2017 Elsevier
Subjects:	Animals arachidonic acid Cilia - genetics Cilia - metabolism Enzyme Activation - genetics Group IV Phospholipases A2 - genetics Group IV Phospholipases A2 - metabolism Hedgehog Proteins - genetics Hedgehog Proteins - metabolism Mice NIH 3T3 Cells phospholipase A2 primary cilium Protein Transport - genetics Signal Transduction Smoothened Smoothened Receptor - genetics Smoothened Receptor - metabolism Sonic Hedgehog arachidonic acid primary cilium Smoothened signal transduction phospholipase A2 Sonic Hedgehog
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Summary:	The G protein-coupled receptor Smoothened (Smo) is the signal transducer of the Sonic Hedgehog (Shh) pathway. Smo signals through G protein-dependent and -independent routes, with G protein-independent canonical signaling to Gli effectors requiring Smo accumulation in the primary cilium. The mechanisms controlling Smo activation and trafficking are not yet clear but likely entail small-molecule binding to pockets in its extracellular cysteine-rich domain (CRD) and/or transmembrane bundle. Here, we demonstrate that the cytosolic phospholipase cPLA2α is activated through Gβγ downstream of Smo to release arachidonic acid. Arachidonic acid binds Smo and synergizes with CRD-binding agonists, promoting Smo ciliary trafficking and high-level signaling. Chemical or genetic cPLA2α inhibition dampens Smo signaling to Gli, revealing an unexpected contribution of G protein-dependent signaling to canonical pathway activity. Arachidonic acid displaces the Smo transmembrane domain inhibitor cyclopamine to rescue CRD agonist-induced signaling, suggesting that arachidonic acid may target the transmembrane bundle to allosterically enhance signaling by CRD agonist-bound Smo. [Display omitted] •Sonic Hedgehog activates cytosolic phospholipase A2 to release arachidonic acid•Phospholipase A2 is activated by Gβγ downstream of Smoothened•Arachidonic acid binds Smoothened to promote its ciliary accumulation and signaling•Arachidonic acid is a candidate allosteric regulator of Smoothened Arensdorf et al. report that phospholipase A2 is activated downstream of the G protein-coupled receptor Smoothened to produce arachidonic acid. Arachidonic acid binds the Smoothened transmembrane domain to promote Smoothened ciliary trafficking and high-level signaling. These results identify arachidonic acid as a candidate allosteric regulator of Smoothened.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead contact
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2017.05.033