ATG9A和ARFIP2共同控制PI4P水平，参与溶酶体修复

IF 10.7 1区生物学 Q1 CELL BIOLOGY

Developmental cell Pub Date : 2025-06-02 DOI:10.1016/j.devcel.2025.05.007

Stefano De Tito, Eugenia Almacellas, Daniel Dai Yu, Emily Millard, Wenxin Zhang, Cecilia de Heus, Christophe Queval, Javier H. Hervás, Enrica Pellegrino, Ioanna Panagi, Ditte Fogde, Teresa L.M. Thurston, Judith Klumperman, Maximiliano Gutierrez, Sharon A. Tooze

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引用次数: 0

摘要

溶酶体损伤激活多种途径来防止溶酶体依赖的细胞死亡，包括涉及内质网(ER)-溶酶体膜接触位点、磷脂酰肌醇4-激酶2a （PI4K2A）、磷脂酰肌醇4-磷酸（PI4P）和固醇结合蛋白样蛋白（OSBPLs）脂质转移蛋白的修复机制。PI4K2A定位于反式高尔基体网络和核内体，但它如何被传递到受损的溶酶体中仍然未知。在急性无菌损伤和细胞内细菌引起的损伤中，我们发现含有atg9a的囊泡在将PI4K2A运送到受损的溶酶体中发挥了关键作用。ADP核糖基化因子相互作用蛋白2 （ARFIP2）是ATG9A囊泡的一个组成部分，它结合并隔离溶酶体上的PI4P，平衡osbsl依赖的脂质转移，并通过受体蛋白复合物-3 （AP-3）的募集促进ATG9A囊泡的回收。我们的研究结果确定了活化的ATG9A囊泡和ARFIP2在损伤和细菌感染后溶酶体稳态中的作用。

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ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair

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ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair

Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving endoplasmic reticulum (ER)-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P), and oxysterol-binding protein-like proteins (OSBPLs) lipid transfer proteins. PI4K2A localizes to the trans-Golgi network and endosomes, yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing OSBPL-dependent lipid transfer and promoting the retrieval of ATG9A vesicles through the recruitment of the adaptor protein complex-3 (AP-3). Our results identify a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.

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来源期刊

Developmental cell 生物-发育生物学

CiteScore

18.90

自引率

1.70%

发文量

203

审稿时长

3-6 weeks

期刊介绍： Developmental Cell, established in 2001, is a comprehensive journal that explores a wide range of topics in cell and developmental biology. Our publication encompasses work across various disciplines within biology, with a particular emphasis on investigating the intersections between cell biology, developmental biology, and other related fields. Our primary objective is to present research conducted through a cell biological perspective, addressing the essential mechanisms governing cell function, cellular interactions, and responses to the environment. Moreover, we focus on understanding the collective behavior of cells, culminating in the formation of tissues, organs, and whole organisms, while also investigating the consequences of any malfunctions in these intricate processes.