Hapalindole Q suppresses autophagosome-lysosome fusion by promoting YAP1 degradation via chaperon- mediated autophagy

• 成果类型: Article
• 署名作者: Wu, Yali; Wang, Shaonan; Guo, Zhicong; Sun, Min; Xu, Zhen; Du, Yu; Zhu, Fahui; Su, Yajuan; Xu, Zhou; Xu, Yi; Gong, Xu; Fang, Ruan; Hu, Jiaojiao; Peng, Yan; Ding, Zhaowen; Liu, Cong; Li, Ang; He, Weiwei
• 署名单位: East China University of Science & Technology; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8549
• DOI: 10.1073/pnas.2400809121
• 发表日期: 2024-12-10
• 关键词: fischerindole; biogenesis; maturation; alkaloids; complex; protein; target

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.