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

  • Nature. 2024 Apr;628(8008):630-638. doi: 10.1038/s41586-024-07249-8.
Letao Li  #  1  2 ,  Xilu Liu  #  1  3 ,  Shanshan Yang  #  1  3 ,  Meijiao Li  2  4 ,  Yanwei Wu  1 ,  Siqi Hu  1  3 ,  Wenjuan Wang  1 ,  Amin Jiang  1 ,  Qianqian Zhang  1 ,  Junbing Zhang  1 ,  Xiaoli Ma  1 ,  Junyan Hu  1 ,  Qiaohong Zhao  2 ,  Yubing Liu  1 ,  Dong Li  1  3 ,  Junjie Hu  1  3 ,  Chonglin Yang  2  4 ,  Wei Feng  5  6 ,  Xiaochen Wang  7  8  9  10
Affiliations
  • 1. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 2. State Key Laboratory of Conservation and Utilization of Bio-Resources in Yunnan, and Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
  • 3. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 4. Southwest United Graduate School, Kunming, China.
  • 5. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 6. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 7. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 8. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 9. Southwest United Graduate School, Kunming, China. [email protected].
  • 10. School of Life Sciences, Southern University of Science and Technology, Shenzhen, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 38538795 DOI: 10.1038/s41586-024-07249-8
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.