小柯机器人

美国匹兹堡大学医学院Toren Finkel和Jay Xiaojun Tan合作发现，磷酸肌醇信号通路介导快速的溶酶体修复。相关论文于2022年9月7日在线发表在《自然》杂志上。

研究人员用一种无偏倚的蛋白质组学方法表明，溶酶体膜透化（LMP）刺激了磷酸肌醇引发的膜拴住和脂质运输（PITT）途径，从而快速修复溶酶体。在LMP之后，磷脂酰肌醇-4激酶2α（PI4K2A）在受损的溶酶体上迅速积累，产生高水平的脂质信使磷脂酰肌醇-4-磷酸。溶酶体磷脂酰肌醇-4-磷酸反过来又招募了多个与氧化甾醇结合蛋白（OSBP）相关的蛋白（ORP）家族成员，包括ORP9、ORP10、ORP11和OSBP，从而协调受损溶酶体和内质网之间广泛的新膜接触点。ORP随后催化磷脂酰丝氨酸和胆固醇从内质网到溶酶体的有力转移，进而支持溶酶体的快速修复。最后，脂质转移蛋白ATG2也被招募到受损的溶酶体，其活性受到磷脂酰丝氨酸的有力刺激。不依赖于巨自噬，ATG2通过直接的溶酶体脂质转移介导快速膜修复。这些研究结果表明，PITT途径可以维持溶酶体膜的完整性，对许多以溶酶体功能受损为特征的年龄相关疾病具有重要意义。

据介绍，溶酶体功能障碍与疾病和正常衰老的关系越来越密切。LMP是溶酶体相关疾病的一个标志，可由不同的细胞压力源触发。鉴于溶酶体的破坏性内容，LMP必须被迅速解决，尽管对其基本机制了解甚少。

附：英文原文

Title: A phosphoinositide signalling pathway mediates rapid lysosomal repair

Author: Tan, Jay Xiaojun, Finkel, Toren

Issue&Volume: 2022-09-07

Abstract: Lysosomal dysfunction has been increasingly linked to disease and normal ageing1,2. Lysosomal membrane permeabilization (LMP), a hallmark of lysosome-related diseases, can be triggered by diverse cellular stressors3. Given the damaging contents of lysosomes, LMP must be rapidly resolved, although the underlying mechanisms are poorly understood. Here, using an unbiased proteomic approach, we show that LMP stimulates a phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair. Upon LMP, phosphatidylinositol-4 kinase type 2α (PI4K2A) accumulates rapidly on damaged lysosomes, generating high levels of the lipid messenger phosphatidylinositol-4-phosphate. Lysosomal phosphatidylinositol-4-phosphate in turn recruits multiple oxysterol-binding protein (OSBP)-related protein (ORP) family members, including ORP9, ORP10, ORP11 and OSBP, to orchestrate extensive new membrane contact sites between damaged lysosomes and the endoplasmic reticulum. The ORPs subsequently catalyse robust endoplasmic reticulum-to-lysosome transfer of phosphatidylserine and cholesterol to support rapid lysosomal repair. Finally, the lipid transfer protein ATG2 is also recruited to damaged lysosomes where its activity is potently stimulated by phosphatidylserine. Independent of macroautophagy, ATG2 mediates rapid membrane repair through direct lysosomal lipid transfer. Together, our findings identify that the PITT pathway maintains lysosomal membrane integrity, with important implications for numerous age-related diseases characterized by impaired lysosomal function.

DOI: 10.1038/s41586-022-05164-4

Source: https://www.nature.com/articles/s41586-022-05164-4

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
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