Streptooctatin A induces autophagy and promotes α-synuclein clearance by directly binding to SUMO2 and inhibiting SUMOylation

Autophagy is a self-degradative process that is essential for cellular homeostasis and survival. Discovery of autophagy-modulatory compounds and the subsequent investigation of their mode of action can provide essential information to understand the factors associated with autophagy and autophagy-related diseases. In this study, we reported a novel autophagy regulator, Streptooctatin A (STR A), which sequentially induces autophagy. Using thermal shift assay, we identified human SUMO2 as a binding candidate of STR A. This interaction was further validated by SPR analysis, with a 16.0 μM of dissociation constant. Additionally, STR A induces autophagy by inhibiting SUMOylation process. Mechanistically, we suggest that STR A-mediated SUMO2 inhibition affects autophagy process through enhancing nuclear translocation of FoxO3a by approximately 1.9-fold, and upregulating autophagy-related genes such as ULK1 and Atg family genes, by 2.19- to 5.26-fold. In cellular Parkinson's disease models, autophagy induction by STR A-mediated deSUMOylation effectively promoted clearance of α-synuclein aggreagates by up to 95 % at 20 μM concentration. Consequently, our findings suggest that STR A is a promising chemical probe for studying SUMO2 function and may serve as a potential therapeutic leads for reducing α-synuclein aggregates in neurodegenerative diseases, especially Parkinson's disease.