The HEAT repeat protein HPO-27 is a lysosome fission factor

• 成果类型: Article
• 署名作者: Li, Letao; Liu, Xilu; Yang, Shanshan; Li, Meijiao; Wu, Yanwei; Hu, Siqi; Wang, Wenjuan; Jiang, Amin; Zhang, Qianqian; Zhang, Junbing; Ma, Xiaoli; Hu, Junyan; Zhao, Qiaohong; Liu, Yubing; Li, Dong; Hu, Junjie; Yang, Chonglin; Feng, Wei; Wang, Xiaochen
• 署名单位: Chinese Academy of Sciences; Institute of Biophysics, CAS; Yunnan University; Yunnan University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Southern University of Science & Technology
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4299
• DOI: 10.1038/s41586-024-07249-8
• 发表日期: 2024-04-18
• 关键词: real-time analysis; membrane fission; life-span; dynamin; accumulation; tubulation; clathrin; conidia; helices; fusion

摘要

Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing1. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission2,3. Little is known about the molecular basis of fission. Here we identify HPO-27, a conserved HEAT repeat protein, as a lysosome scission factor in Caenorhabditis elegans. Loss of HPO-27 impairs lysosome fission and leads to an excessive tubular network that ultimately collapses. HPO-27 and its human homologue MROH1 are recruited to lysosomes by RAB-7 and enriched at scission sites. Super-resolution imaging, negative-staining electron microscopy and in vitro reconstitution assays reveal that HPO-27 and MROH1 self-assemble to mediate the constriction and scission of lysosomal tubules in worms and mammalian cells, respectively, and assemble to sever supported membrane tubes in vitro. Loss of HPO-27 affects lysosomal morphology, integrity and degradation activity, which impairs animal development and longevity. Thus, HPO-27 and MROH1 act as self-assembling scission factors to maintain lysosomal homeostasis and function. The conserved HEAT repeat protein HPO-27 is identified as a lysosome scission factor in Caenorhabditis elegans, and the human homologue MROH1 also serves the same function to maintain lysosomal homeostasis.