National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
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.
Nature. 2024 Apr;628(8008):630-638. doi: 10.1038/s41586-024-07249-8. Epub 2024 Mar 27.
Lysosomes are degradation and signalling centres crucial for homeostasis, development and ageing. To meet diverse cellular demands, lysosomes remodel their morphology and function through constant fusion and fission. 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.
溶酶体是维持体内平衡、发育和衰老的关键降解和信号中心。为了满足细胞的多样化需求，溶酶体通过不断的融合和分裂来重塑其形态和功能。关于分裂的分子基础知之甚少。在这里，我们确定 HPO-27 是秀丽隐杆线虫中溶酶体分裂的一个保守的 HEAT 重复蛋白因子。HPO-27 的缺失会损害溶酶体的分裂，导致过度的管状网络最终崩溃。HPO-27 和它的人类同源物 MROH1 被 RAB-7 招募到溶酶体，并在分裂部位富集。超分辨率成像、负染电子显微镜和体外重建实验表明，HPO-27 和 MROH1 自我组装分别介导线虫和哺乳动物细胞中溶酶体小管的收缩和分裂，并在体外组装以切断支持的膜管。HPO-27 的缺失会影响溶酶体的形态、完整性和降解活性，从而损害动物的发育和寿命。因此，HPO-27 和 MROH1 作为自组装的分裂因子，维持溶酶体的体内平衡和功能。
