Systems Biology Group, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
Systems Biology Group, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.
EMBO J. 2018 Mar 1;37(5). doi: 10.15252/embj.201797597. Epub 2018 Jan 8.
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions form functionally active microdomains that connect intracellular and extracellular environments. While the key role of these interfaces in maintenance of intracellular Ca levels has been uncovered in recent years, the functional significance of ER-PM junctions in non-excitable cells has remained unclear. Here, we show that the ER calcium sensor protein STIM1 (stromal interaction molecule 1) interacts with the plasma membrane-localized adenylyl cyclase 6 (ADCY6) to govern melanogenesis. The physiological stimulus α-melanocyte-stimulating hormone (αMSH) depletes ER Ca stores, thus recruiting STIM1 to ER-PM junctions, which in turn activates ADCY6. Using zebrafish as a model system, we further established STIM1's significance in regulating pigmentation STIM1 domain deletion studies reveal the importance of Ser/Pro-rich C-terminal region in this interaction. This mechanism of cAMP generation creates a positive feedback loop, controlling the output of the classical αMSH-cAMP-MITF axis in melanocytes. Our study thus delineates a signaling module that couples two fundamental secondary messengers to drive pigmentation. Given the central role of calcium and cAMP signaling pathways, this module may be operative during various other physiological processes and pathological conditions.
内质网（ER）-质膜（PM）连接形成功能活跃的微区，连接细胞内和细胞外环境。近年来，虽然这些界面在维持细胞内 Ca 水平方面的关键作用已经被揭示，但 ER-PM 连接在非兴奋细胞中的功能意义仍然不清楚。在这里，我们表明内质网钙传感器蛋白 STIM1（基质相互作用分子 1）与位于质膜的腺苷酸环化酶 6（ADCY6）相互作用，以调节黑色素生成。生理刺激物 α-黑色素细胞刺激素（αMSH）耗尽 ER Ca 储存，从而募集 STIM1 到 ER-PM 连接，这反过来又激活 ADCY6。我们使用斑马鱼作为模型系统，进一步确定了 STIM1 在调节色素沉着中的重要性。STIM1 结构域缺失研究揭示了 Ser/Pro 丰富的 C 末端区域在这种相互作用中的重要性。这种 cAMP 生成机制创建了一个正反馈回路，控制黑色素细胞中经典的 αMSH-cAMP-MITF 轴的输出。因此，我们的研究描绘了一个信号模块，将两种基本的第二信使耦合起来，以驱动色素沉着。鉴于钙和 cAMP 信号通路的核心作用，该模块在其他各种生理过程和病理条件下可能起作用。
