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

• Published in: Nature (London) 2024-04, Vol.628 (8008), p.630-638
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: 14/19; 14/28; 14/35; 14/63; 38/109; 38/35; 38/70; 38/89; 631/136/7; 631/80/313/2377; 631/80/642/1624; 64/11; 82/1; Acidification; Adults; Animals; Autophagy; Caenorhabditis elegans; Caenorhabditis elegans Proteins - metabolism; Chromatin; Cleavage; Cytology; Degradation; Homeostasis; Hot Temperature; Humanities and Social Sciences; Humans; Integrity; Kinases; Lysosomes - metabolism; Mammals - metabolism; Microscopy; Mitochondria; Morphology; multidisciplinary; Mutation; Phagocytes; Phagolysosomes; Phenotypes; Proteins; Science; Science (multidisciplinary); Self-assembly; Signal Transduction; Worms
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-024-07249-8

Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing 1 . To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission 2 , 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.