SAC-1 ensures epithelial endocytic recycling by restricting ARF-6 activity.
SAC-1 ensures epithelial endocytic recycling by restricting ARF-6 activity.
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SAC-1 通过限制 ARF-6 活性来确保上皮内吞再循环。
DOI：
10.1083/jcb.201711065
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发表时间：
2018-06-04
期刊：
影响因子：
--
通讯作者：
Shi A
中科院分区：
文献类型：
--
作者：
Chen D;Yang C;Liu S;Hang W;Wang X;Chen J;Shi A
Arf 6/ARF-6是内吞再循环中内体PI（4，5）P2库的关键调节剂。Chen等表明SAC-1对C.优雅的SAC-1是ARF-6的一个新的相互作用者，通过限制ARF-6（国内生产总值）使用其GEF BRIS-1来抑制ARF-6的活动。Arf 6/ARF-6是内吞再循环中内体磷脂酰肌醇4，5-二磷酸（PI（4，5）P2）库的关键调节剂。为了进一步表征ARF-6调节，我们在秀丽隐杆线虫中进行了ARF-6相互作用筛选，并鉴定了SAC-1，即酵母中磷酸肌醇磷酸酶Sac 1 p的同源物，作为一种新的ARF-6伴侣。在不存在ARF-6的情况下，基底外侧内体显示上皮细胞中SAC-1染色的损失。稳态货物分布分析表明，SAC-1的损失特别影响顶端分泌交付和基底外侧循环。PI（4，5）P2水平和ARF-6效应子SAF-16的内体标记在SAC-1突变体中显著升高，表明SAC-1作为ARF-6的负调节剂发挥作用。进一步的分析表明，SAC-1和ARF-6-GEF BRIS-1之间存在相互作用。这种相互作用以浓度依赖性方式胜过ARF-6（鸟苷二磷酸[GDP]）与BRIS-1的结合。因此，SAC-1的缺失促进了ARF-6和BRIS-1之间的细胞内重叠。BRIS-1敲低导致SAC-1耗尽的细胞中PI（4，5）P2水平的显著降低。有趣的是，SAC-1在螯合BRIS-1中的作用与SAC-1的催化活性无关。我们的结果表明，SAC-1与ARF-6的相互作用通过限制ARF-6（GDP）对其鸟嘌呤核苷酸交换因子BRIS-1的访问来抑制ARF-6的活性。
Arf6/ARF-6 is a crucial regulator of the endosomal PI(4,5)P2 pool in endocytic recycling. Chen et al. show that SAC-1 is important for epithelial cell recycling in C. elegans. SAC-1 acts as a novel interactor for ARF-6, curbing ARF-6 activity by limiting the access of ARF-6(GDP) to its GEF BRIS-1. Arf6/ARF-6 is a crucial regulator of the endosomal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) pool in endocytic recycling. To further characterize ARF-6 regulation, we performed an ARF-6 interactor screen in Caenorhabditis elegans and identified SAC-1, the homologue of the phosphoinositide phosphatase Sac1p in yeast, as a novel ARF-6 partner. In the absence of ARF-6, basolateral endosomes show a loss of SAC-1 staining in epithelial cells. Steady-state cargo distribution assays revealed that loss of SAC-1 specifically affected apical secretory delivery and basolateral recycling. PI(4,5)P2 levels and the endosomal labeling of the ARF-6 effector UNC-16 were significantly elevated in sac-1 mutants, suggesting that SAC-1 functions as a negative regulator of ARF-6. Further analyses revealed an interaction between SAC-1 and the ARF-6-GEF BRIS-1. This interaction outcompeted ARF-6(guanosine diphosphate [GDP]) for binding to BRIS-1 in a concentration-dependent manner. Consequently, loss of SAC-1 promotes the intracellular overlap between ARF-6 and BRIS-1. BRIS-1 knockdown resulted in a significant reduction in PI(4,5)P2 levels in SAC-1-depleted cells. Interestingly, the action of SAC-1 in sequestering BRIS-1 is independent of SAC-1’s catalytic activity. Our results suggest that the interaction of SAC-1 with ARF-6 curbs ARF-6 activity by limiting the access of ARF-6(GDP) to its guanine nucleotide exchange factor, BRIS-1.
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