用于溶酶体修复的ESCRT组件激光偶损伤传感
加州大学Roberto Zoncu团队在研究中取得进展。他们的论文发现了用于溶酶体修复的ESCRT组件激光偶损伤传感。2026年6月3日出版的《自然》发表了这项成果。
在损伤敏感的遗传背景下，利用全基因组CRISPRi筛选，该课题组确定了LC3/ GABARAP辅助的ESCRT募集刺激因子（LASER），这是一种多组分蛋白质组装，当钙从受损的溶酶体释放出来时迅速形成，并将溶酶体膜损伤的感应偶联到ESCRT依赖性修复中。LASER的核心是TFG，一种内质网出口位点蛋白，通过与溶酶体磷脂结合的ATG8家族蛋白（LC3和GABARAP）结合，易位到受损的溶酶体。ATG8结合的TFG形成寡聚体，通过亲和驱动的相互作用增强的保守基序识别，直接招募ESCRT-I基本亚基TSG101。TFG结合TSG101刺激ESCRT-I-II-III聚合并促进膜修复。导致遗传性痉挛性截瘫的TFG突变破坏了其寡聚化，损害了溶酶体ESCRT的募集和膜的重封，暗示缺陷修复是TFG相关神经变性的驱动因素。然后，LASER促进ESCRT在受损溶酶体上的聚合，并将损伤传感与膜修复结合起来。
据悉，溶酶体膜完整性对细胞存活至关重要，但损伤感知如何在时空上与修复耦合仍然知之甚少。运输所需的内体分选复合物（ESCRT） I-III的募集和组装迅速抵消膜损伤，但ESCRT-I如何识别有缺陷的溶酶体膜尚不清楚。
附：英文原文
Title: LASER couples damage sensing to ESCRT assembly for lysosome repair
Author: Goul, Claire S., Jain, Aakriti, Yitiz, Samira, Soltani, Zahra E., Yang, Serim, Rapp, Simon, Spacci, Martina, Federman, Scot, Sacco, James, Li, Huinan, Enriquez, Lauren D., Liv, Nalan, Przybyla, Laralynne, Zoncu, Roberto
Issue&Volume: 2026-06-03
Abstract: Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I–III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I–II–III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
DOI: 10.1038/s41586-026-10604-6
Source: https://www.nature.com/articles/s41586-026-10604-6
期刊信息
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
投稿链接：http://www.nature.com/authors/submit_manuscript.html
