文献类型：期刊文献

英文题名：Hapalindole Q suppresses autophagosome-lysosome fusion by promoting YAP1 degradation via chaperon- mediated autophagy

作者：Wu, Yali[1];Wang, Shaonan[1];Guo, Zhicong[2];Sun, Min[1];Xu, Zhen[1];Du, Yu[2];Zhu, Fahui[1];Su, Yajuan[1];Xu, Zhou[2];Xu, Yi[2];Gong, Xu[2];Fang, Ruan[1,2];Hu, Jiaojiao[2,3];Peng, Yan[1];Ding, Zhaowen[1];Liu, Cong[2,3];Li, Ang[2];He, Weiwei[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China;[3]Chinese Acad Sci, Interdisciplinary Res Ctr Biol & Chem, Shanghai Inst Organ Chem, Shanghai 201210, Peoples R China

年份：2024

卷号：121

期号：50

外文期刊名：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001379593400001)】；

基金：We thank Profs. Zhen Yang, Hu Zhou, Qian Meng, Chen-Ying Liu, Lifeng Pan, Hai Jiang, Chu Wang, and Wenqing Shui for discussions. We are also grateful to Dr. Chen Su of the Mass Spectrometry System and the staff of the Large-Scale Protein Production Unit at the National Facility for Protein Science Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Sciences for their assistance with data collection and analysis. This work was supported by the National Natural Science Foundation of China (21931014, 22477026, U2002221, 21572064, and 81502956) , Chinese Academy of Sciences (YSBR-095, XDB1060000, XBZG-ZDSYS-202303, and 121731KYSB20190039) , and Science and Technology Commission of Shanghai Municipality (JCYJ-SHFY-2022-005, 15PJ1401300, and 20430713400) . A.L. is grateful to the New Cornerstone Science Foundation for the Xplorer Prize.

语种：英文

外文关键词：natural product; autophagy inhibitor; YAP1 degradation; chaperone- mediated autophagy

摘要：Autophagy is a conserved catabolic process crucial for maintaining cellular homeostasis and has emerged as a promising therapeutic target for many diseases. Mechanistically novel small- molecule autophagy regulators are highly desirable from a pharmacological point of view. Here, we report the macroautophagy- inhibitory effect of hapalindole Q, a member of the structurally intriguing but biologically understudied hapalindole family of indole terpenoids. This compound promotes the noncanonical degradation of Yes- associated protein 1 (YAP1), the downstream effector of the Hippo signaling pathway, via chaperone- mediated autophagy, disrupting proper distribution of Rab7 and suppressing autophagosome-lysosome fusion in macroautophagy. Its binding to YAP1 is further confirmed by using biophysical techniques. A preliminary structure-activity relationship study reveals that the hapalindole Q scaffold, rather than the isothiocyanate group, is essential for YAP1 binding and degradation. This work not only identifies a macroautophagy inhibitor with a distinct mechanism of action but also provided a molecular scaffold for direct targeting of YAP1, which may benefit the development of therapeutics for both autophagy- related and Hippo-YAP- related diseases.