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AP-3-dependent targeting of flippase ATP8A1 to lamellar bodies suppresses activation of YAP in alveolar epithelial type 2 cells [Cell Biology]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2021-05-18 , DOI: 10.1073/pnas.2025208118
Seunghyi Kook 1 , Ping Wang 1 , Shufang Meng 1 , Christopher S Jetter 1 , Jennifer M S Sucre 1 , John T Benjamin 1 , Jason J Gokey 2 , Hayley A Hanby 3, 4, 5, 6 , Alexa Jaume 3 , Laura Goetzl 7 , Michael S Marks 3, 4, 5 , Susan H Guttentag 8
Affiliation  

Lamellar bodies (LBs) are lysosome-related organelles (LROs) of surfactant-producing alveolar type 2 (AT2) cells of the distal lung epithelium. Trafficking pathways to LBs have been understudied but are likely critical to AT2 cell homeostasis given associations between genetic defects of endosome to LRO trafficking and pulmonary fibrosis in Hermansky Pudlak syndrome (HPS). Our prior studies uncovered a role for AP-3, defective in HPS type 2, in trafficking Peroxiredoxin-6 to LBs. We now show that the P4-type ATPase ATP8A1 is sorted by AP-3 from early endosomes to LBs through recognition of a C-terminal dileucine-based signal. Disruption of the AP-3/ATP8A1 interaction causes ATP8A1 accumulation in early sorting and/or recycling endosomes, enhancing phosphatidylserine exposure on the cytosolic leaflet. This in turn promotes activation of Yes-activating protein, a transcriptional coactivator, augmenting cell migration and AT2 cell numbers. Together, these studies illuminate a mechanism whereby loss of AP-3–mediated trafficking contributes to a toxic gain-of-function that results in enhanced and sustained activation of a repair pathway associated with pulmonary fibrosis.



中文翻译:

AP-3 依赖性靶向翻转酶 ATP8A1 至层状体抑制肺泡上皮 2 型细胞中 YAP 的激活 [细胞生物学]

层状体 (LBs) 是远端肺上皮的产生表面活性剂的肺泡 2 型 (AT2) 细胞的溶酶体相关细胞器 (LRO)。LBs 的运输途径尚未得到充分研究,但考虑到内体遗传缺陷与 LRO 运输和 Hermansky Pudlak 综合征 (HPS) 肺纤维化之间的关联,可能对 AT2 细胞稳态至关重要。我们之前的研究揭示了 AP-3(HPS 2 型缺陷)在将 Peroxiredoxin-6 运输到 LB 中的作用。我们现在表明,P4 型 ATP 酶 ATP8A1 由 AP-3 通过识别基于 C 末端双亮氨酸的信号从早期内体到 LBs 进行分类。AP-3/ATP8A1 相互作用的破坏会导致 ATP8A1 在早期分选和/或回收内体中积累,从而增强磷脂酰丝氨酸在胞质小叶上的暴露。这反过来又促进了 Yes 激活蛋白(一种转录共激活因子)的激活,增加了细胞迁移和 AT2 细胞数量。总之,这些研究阐明了一种机制,即 AP-3 介导的运输损失导致毒性功能获得,导致与肺纤维化相关的修复途径增强和持续激活。

更新日期:2021-05-15
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