Abstract
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.