BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells.
BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells.
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DOI：
10.1074/jbc.ra120.015680
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发表时间：
2020-12-25
期刊：
影响因子：
--
通讯作者：
Sessa WC
中科院分区：
文献类型：
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作者：
Tao B;Kraehling JR;Ghaffari S;Ramirez CM;Lee S;Fowler JW;Lee WL;Fernandez-Hernando C;Eichmann A;Sessa WC
骨形态发生蛋白-9（BMP-9）是一种循环细胞因子，已知其在内皮稳态中起重要作用，BMP-9与受体激活素样激酶1（ALK-1）的结合促进内皮细胞静止。以前，我们使用无偏筛选，将ALK-1鉴定为内皮细胞中低密度脂蛋白（LDL）的高容量受体，以非降解方式介导其转胞吞作用。在这里，我们研究了BMP-9和LDL之间的串扰以及它如何影响它们与ALK-1的相互作用。用BMP-9处理内皮细胞触发ALK-1的广泛内吞作用，并且其由小窝蛋白-1（CAV-1）和发动蛋白-2（DNM 2）介导，而不是网格蛋白重链。CAV-1的敲低降低了BMP-9介导的ALK-1内化、BMP-9依赖性信号传导和基因表达。类似地，用LDL处理内皮细胞减少BMP-9诱导的SMAD 1/5磷酸化和CAV-1和DNM 2的基因表达和沉默减少LDL介导的ALK-1内化。有趣的是，BMP-9介导的ALK-1内化强烈降低LDL转胞吞作用至ALK-1缺乏时的水平。因此，BMP-9水平可以通过CAV-1控制ALK-1的细胞表面水平，以调节BMP-9信号传导和LDL转胞吞作用。
Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9–mediated internalization of ALK-1, BMP-9–dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9–induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9–mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.