Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation

Publication date: 6 June 2017
Source:Cell Reports, Volume 19, Issue 10
Author(s): Angela M. Arensdorf, Miriam E. Dillard, Jacob M. Menke, Matthew W. Frank, Charles O. Rock, Stacey K. Ogden
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.

Graphical abstract

Teaser

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.


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