A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation

• 成果类型: Article
• 署名作者: Knyazeva, Anastasia; Li, Shuang; Corkery, Dale P.; Shankar, Kasturika; Herzog, Laura K.; Zhang, Xuepei; Singh, Birendra; Niggemeyer, Georg; Grill, David; Gilthorpe, Jonathan D.; Gaetani, Massimiliano; Carlson, Lars- Anders; Waldmann, Herbert; Wu, Yao-Wen
• 署名单位: Umea University; Umea University; Umea University; Umea University; Umea University; Karolinska Institutet; Umea University; Max Planck Society; Umea University; Dortmund University of Technology
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9804
• DOI: 10.1073/pnas.2317680121
• 发表日期: 2024-04-23
• 关键词: multivesicular body pathway; escrt-iii; membrane scission; structural basis; v-atpase; complex; spastin; ist1

摘要

The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1 - CHMP1B within the ESCRT - III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1 - CHMP1B copolymers essential for normal - topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1 - CHMP1B complex.