Li Qian, Cai Wei-Jie, Ji Yong-Hua, Feng Xing-Hua
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China.
Institute of Biofilm and Biomedicine, Shanghai University, Shanghai 200444, China.
Sheng Li Xue Bao. 2021 Feb 25;73(1):137-142.
Rapamycin (Rap) is an immunosuppressant, which is mainly used in the anti-rejection of organ transplantation. Meanwhile, it also shows great potential in the fields of anticancer, neuroprotection and anti-aging. Rap can inhibit the activity of mammalian target of Rap (mTOR). It activates the transcription factor EB (TFEB) to up-regulate lysosomal function and eliminates the inhibitory effect of mTOR on ULK1 (unc-51 like autophagy activating kinase 1) to promote autophagy. Recent research showed that Rap can directly activate the lysosomal cation channel TRPML1 in an mTOR-independent manner. TRPML1 activation releases lysosomal calcium. Calcineurin functions as the sensor of the lysosomal calcium signal and activates TFEB, thus promoting lysosome function and autophagy. This finding has greatly broadened and deepened our understanding of the pharmacological roles of Rap. In this review, we briefly introduce the canonical Rap-mTOR-ULK1/TFEB signaling pathway, and then discuss the discovery of TRPML1 as a new target of Rap and the pharmacological potential of this novel Rap-TRPML1-Calcineurin-TFEB pathway.
雷帕霉素（Rap）是一种免疫抑制剂，主要用于器官移植的抗排斥反应。同时，它在抗癌、神经保护和抗衰老领域也显示出巨大潜力。Rap可抑制雷帕霉素哺乳动物靶蛋白（mTOR）的活性。它激活转录因子EB（TFEB）以上调溶酶体功能，并消除mTOR对ULK1（类unc-51自噬激活激酶1）的抑制作用以促进自噬。最近的研究表明，Rap可以不依赖mTOR的方式直接激活溶酶体阳离子通道TRPML1。TRPML1的激活会释放溶酶体钙。钙调神经磷酸酶作为溶酶体钙信号的传感器并激活TFEB，从而促进溶酶体功能和自噬。这一发现极大地拓宽和加深了我们对Rap药理作用的理解。在本综述中，我们简要介绍了经典的Rap-mTOR-ULK1/TFEB信号通路，然后讨论了TRPML1作为Rap新靶点的发现以及这条新的Rap-TRPML1-钙调神经磷酸酶-TFEB通路的药理潜力。
