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

Letao Li, Xilu Liu, Shanshan Yang, Meijiao Li, Yanwei Wu, Siqi Hu, Wenjuan Wang, Amin Jiang, Qianqian Zhang, Junbing Zhang, Xiaoli Ma, Junyan Hu, Qiaohong Zhao, Yubing Liu, Dong Li, Junjie Hu, Chonglin Yang, Wei Feng () and Xiaochen Wang ()
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Letao Li: Chinese Academy of Sciences
Xilu Liu: Chinese Academy of Sciences
Shanshan Yang: Chinese Academy of Sciences
Meijiao Li: Yunnan University
Yanwei Wu: Chinese Academy of Sciences
Siqi Hu: Chinese Academy of Sciences
Wenjuan Wang: Chinese Academy of Sciences
Amin Jiang: Chinese Academy of Sciences
Qianqian Zhang: Chinese Academy of Sciences
Junbing Zhang: Chinese Academy of Sciences
Xiaoli Ma: Chinese Academy of Sciences
Junyan Hu: Chinese Academy of Sciences
Qiaohong Zhao: Yunnan University
Yubing Liu: Chinese Academy of Sciences
Dong Li: Chinese Academy of Sciences
Junjie Hu: Chinese Academy of Sciences
Chonglin Yang: Yunnan University
Wei Feng: Chinese Academy of Sciences
Xiaochen Wang: Chinese Academy of Sciences

Nature, 2024, vol. 628, issue 8008, 630-638

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07249-8

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