Venkatapurapu Sai Phanindra, Kelley Joshua B, Dixit Gauri, Pena Matthew, Errede Beverly, Dohlman Henrik G, Elston Timothy C
Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
Mol Biol Cell. 2015 Nov 5;26(22):4124-34. doi: 10.1091/mbc.E14-12-1635. Epub 2015 Aug 26.
G protein-coupled receptor (GPCR) signaling is fundamental to physiological processes such as vision, the immune response, and wound healing. In the budding yeast Saccharomyces cerevisiae, GPCRs detect and respond to gradients of pheromone during mating. After pheromone stimulation, the GPCR Ste2 is removed from the cell membrane, and new receptors are delivered to the growing edge. The regulator of G protein signaling (RGS) protein Sst2 acts by accelerating GTP hydrolysis and facilitating pathway desensitization. Sst2 is also known to interact with the receptor Ste2. Here we show that Sst2 is required for proper receptor recovery at the growing edge of pheromone-stimulated cells. Mathematical modeling suggested pheromone-induced synthesis of Sst2 together with its interaction with the receptor function to reestablish a receptor pool at the site of polarized growth. To validate the model, we used targeted genetic perturbations to selectively disrupt key properties of Sst2 and its induction by pheromone. Together our results reveal that a regulator of G protein signaling can also regulate the G protein-coupled receptor. Whereas Sst2 negatively regulates G protein signaling, it acts in a positive manner to promote receptor retention at the growing edge.
G蛋白偶联受体（GPCR）信号传导对于诸如视觉、免疫反应和伤口愈合等生理过程至关重要。在出芽酵母酿酒酵母中，GPCR在交配过程中检测并响应信息素梯度。信息素刺激后，GPCR Ste2从细胞膜上移除，新的受体被递送到生长边缘。G蛋白信号传导调节因子（RGS）蛋白Sst2通过加速GTP水解和促进信号通路脱敏来发挥作用。已知Sst2也与受体Ste2相互作用。在这里，我们表明Sst2是信息素刺激细胞生长边缘正确回收受体所必需的。数学模型表明，信息素诱导的Sst2合成及其与受体的相互作用有助于在极化生长部位重新建立受体库。为了验证该模型，我们使用靶向基因扰动来选择性破坏Sst2的关键特性及其由信息素诱导的特性。我们的结果共同表明，一种G蛋白信号传导调节因子也可以调节G蛋白偶联受体。虽然Sst2对G蛋白信号传导起负调节作用，但它以积极的方式促进受体在生长边缘的保留。
