2. Academic Validation
  3. CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis

CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis

  • Nat Commun. 2020 Sep 21;11(1):4765. doi: 10.1038/s41467-020-18565-8.
Jian-Wei Hao  # 1,  Juan Wang  # 1 2,  Huiling Guo  # 1,  Yin-Yue Zhao 1,  Hui-Hui Sun 1,  Yi-Fan Li 1,  Xiao-Ying Lai 1,  Ning Zhao 1,  Xu Wang 2,  Changchuan Xie 1,  Lixin Hong 1,  Xi Huang 1,  Hong-Rui Wang 1 3,  Cheng-Bin Li 4,  Bin Liang 4,  Shuai Chen 5,  Tong-Jin Zhao 6 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, Fujian, China.
  • 2 Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
  • 3 State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, 361102, Fujian, China.
  • 4 Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, 650091, China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Pukou District, Nanjing, 210061, China. chenshuai@nju.edu.cn.
  • 6 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 361102, Fujian, China. zhaotj@fudan.edu.cn.
  • 7 Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China. zhaotj@fudan.edu.cn.
  • 8 State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, 361102, Fujian, China. zhaotj@fudan.edu.cn.
  • # Contributed equally.
PMID: 32958780 DOI: 10.1038/s41467-020-18565-8
Abstract

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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