Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation.
Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation.
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DOI：
10.1016/j.celrep.2017.05.033
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发表时间：
2017-06-06
期刊：
影响因子：
8.8
通讯作者：
Ogden SK
中科院分区：
文献类型：
--
作者：
Arensdorf AM;Dillard ME;Menke JM;Frank MW;Rock CO;Ogden SK
G蛋白偶联受体平滑(Smo)是Sonic Hedgehog(Shh)途径的信号转导。SMO信号通过G蛋白依赖和独立的途径，G蛋白不依赖的典型信号传递到Gli效应器，需要在初级纤毛中积累Smo。控制Smo激活和运输的机制尚不清楚，但可能需要小分子结合到其胞外富含半胱氨酸的区域(CRD)和/或跨膜束的口袋上。在这里，我们证明了胞浆磷脂酶cPLA2α通过Smo下游的Gβγ被激活以释放花生四烯酸。花生四烯酸与Smo结合，并与CRD结合激动剂协同作用，促进Smo纤毛转运和高水平信号转导。化学或遗传的cPLA2α抑制抑制了Smo对Gli的信号转导，揭示了G蛋白依赖的信号转导对典型途径活性的意外贡献。花生四烯酸取代Smo跨膜区抑制剂环丙胺来拯救CRD激动剂诱导的信号转导，提示花生四烯酸可能靶向跨膜束，通过CRD激动剂结合的Smo变构增强信号转导。Arensdorf等人报道，磷脂酶A2在G蛋白偶联受体平滑的下游被激活，以产生花生四烯酸。花生四烯酸结合光滑的跨膜区，促进光滑的纤毛运输和高水平的信号转导。这些结果表明花生四烯酸是Smoothened的候选变构调节剂。
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. 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. Herein we demonstrate cytosolic phospholipase cPLA2α is activated through Gβγ downstream of Smo to release arachidonic acid. Arachidonic acid binds Smo and synergizes with CRD-binding agonist, 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 arachidonic acid may target the transmembrane bundle to allosterically enhance signaling by CRD agonist-bound Smo. Arensdorf et al report 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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影响因子：
13.8
作者：
Arensdorf AM;Marada S;Ogden SK
通讯作者：
Ogden SK
影响因子：
5.5
作者：
Bechler ME;Brown WJ
通讯作者：
Brown WJ
影响因子：
3.7
作者：
Jung B;Padula D;Burtscher I;Landerer C;Lutter D;Theis F;Messias AC;Geerlof A;Sattler M;Kremmer E;Boldt K;Ueffing M;Lickert H
通讯作者：
Lickert H
影响因子：
3.5
作者：
Balsinde, J;Winstead, MV;Dennis, EA
通讯作者：
Dennis, EA
影响因子：
2.9
作者：
Duvernay, Matthew T.;Matafonov, Anton;Hamm, Heidi E.
通讯作者：
Hamm, Heidi E.