CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis.
CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis.
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CD36 通过动态棕榈酰化调节的内吞作用促进脂肪酸摄取
DOI：
10.1038/s41467-020-18565-8
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发表时间：
2020-09-21
影响因子：
16.6
通讯作者：
Zhao TJ
中科院分区：
文献类型：
--
作者：
Hao JW;Wang J;Guo H;Zhao YY;Sun HH;Li YF;Lai XY;Zhao N;Wang X;Xie C;Hong L;Huang X;Wang HR;Li CB;Liang B;Chen S;Zhao TJ
脂肪酸（FAs）是必需的营养素，但它们如何被转运到细胞中仍不清楚。在这里，我们表明，脂肪酸触发小窝依赖的CD36内化，这反过来又提供脂肪酸进入脂肪细胞。在此过程中，FA与CD 36的结合激活其下游激酶林恩，该激酶磷酸化DHHC 5（CD 36的棕榈酰酰基转移酶）在Tyr 91处并使其失活。CD 36然后被APT 1脱棕榈酰化并募集另一个酪氨酸激酶SYK磷酸化JNK和VAV以启动FA的内吞摄取。通过抑制APT1、林恩或SYK阻断CD 36内化可消除CD 36依赖性FA摄取。将CD36限制在棕榈酰化或脱棕榈酰化状态消除其FA摄取活性，表明CD36的动态棕榈酰化的重要作用。此外，通过靶向林恩或SYK阻断内吞作用抑制脂肪细胞中的CD 36依赖性脂滴生长和高脂饮食诱导的小鼠体重增加。我们的研究揭示了一个动态的棕榈酰化调节的内吞途径，以采取脂肪酸。
Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.
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