STEEP介導STING出內質網並激活信號通路
作者：
小柯機器人發布時間：2020/7/22 13:48:07
丹麥奧爾胡斯大學Sren R. Paludan研究團隊在研究中取得進展。他們探明了STEEP介導STING 出內質網（ER）並激活信號。相關論文發表在2020年7月20日的《自然-免疫學》雜誌上。
研究人員發現STEEP是STING信號的正調控因子。STEEP與STING有關，並促進了其在ER的運輸。這是通過誘導磷脂醯肌醇-3-磷酸（PtdIns（3）P）的產生和ER膜曲率形成實現的，從而引起COPII調控的STING從ER到高爾基體的運輸。STEEP缺失會損害STING相關疾病患者腦組織和細胞中的病毒感染，從而削弱了STING誘導的基因表達。有趣的是，來自患者STING功能獲得的突變體與STEEP強烈相互作用，從而導致ER PtdIns（3）P水平和膜曲率增加。因此，STEEP通過促進STING出ER來激活此信號通路。
據了解，STING對於預防感染和進行腫瘤免疫監控必不可少，但它也可以誘發病理性炎症。STING駐留在ER上，並在刺激後發生信號傳導實現ERGIC /高爾基體上運輸。儘管STING 出ER是STING信號通路中的限速步驟，但誘發此過程的機制尚不清楚。
附：英文原文
Title: STEEP mediates STING ER exit and activation of signaling
Author: Bao-cun Zhang, Ramya Nandakumar, Line S. Reinert, Jinrong Huang, Anders Laustsen, Zong-liang Gao, Cheng-long Sun, Sren Beck Jensen, Anne Troldborg, Sonia Assil, Martin F. Berthelsen, Carsten Scavenius, Yan Zhang, Samuel J. Windross, David Olagnier, Thaneas Prabakaran, Chiranjeevi Bodda, Ryo Narita, Yujia Cai, Cong-gang Zhang, Harald Stenmark, Christine M. Doucet, Takeshi Noda, Zheng Guo, Raphaela Goldbach-Mansky, Rune Hartmann, Zhijian J. Chen, Jan J. Enghild, Rasmus O. Bak, Martin K. Thomsen, Sren R. Paludan
Issue&Volume: 2020-07-20
Abstract: STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.
DOI: 10.1038/s41590-020-0730-5
Source: https://www.nature.com/articles/s41590-020-0730-5