CD36 Facilitates Fatty Acid Uptake by Dynamic Palmitoylation-regulated Endocytosis

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Sep 22

PMID 32958780

Citations 137

Authors

Jian-Wei Hao

Juan Wang

Huiling Guo

Yin-Yue Zhao

Hui-Hui Sun

Yi-Fan Li

Xiao-Ying Lai

Ning Zhao

Xu Wang

Changchuan Xie

Lixin Hong

Xi Huang

Hong-Rui Wang

Cheng-Bin Li

Bin Liang

Shuai Chen

Tong-Jin Zhao

Affiliations

Soon will be listed here.

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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References

McArthur M, Atshaves B, Frolov A, Foxworth W, Kier A, Schroeder F . Cellular uptake and intracellular trafficking of long chain fatty acids. J Lipid Res. 1999; 40(8):1371-83. View

Hamilton J . Fatty acid transport: difficult or easy?. J Lipid Res. 1998; 39(3):467-81. View

Hamilton J . Fast flip-flop of cholesterol and fatty acids in membranes: implications for membrane transport proteins. Curr Opin Lipidol. 2003; 14(3):263-71. DOI: 10.1097/00041433-200306000-00006. View

Hajri T, Abumrad N . Fatty acid transport across membranes: relevance to nutrition and metabolic pathology. Annu Rev Nutr. 2002; 22:383-415. DOI: 10.1146/annurev.nutr.22.020402.130846. View

Ehehalt R, Fullekrug J, Pohl J, Ring A, Herrmann T, Stremmel W . Translocation of long chain fatty acids across the plasma membrane--lipid rafts and fatty acid transport proteins. Mol Cell Biochem. 2006; 284(1-2):135-40. DOI: 10.1007/s11010-005-9034-1. View

Pepino M, Kuda O, Samovski D, Abumrad N . Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu Rev Nutr. 2014; 34:281-303. PMC: 4329921. DOI: 10.1146/annurev-nutr-071812-161220. View

Su X, Abumrad N . Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009; 20(2):72-7. PMC: 2845711. DOI: 10.1016/j.tem.2008.11.001. View

Pohl J, Ring A, Korkmaz U, Ehehalt R, Stremmel W . FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. Mol Biol Cell. 2004; 16(1):24-31. PMC: 539148. DOI: 10.1091/mbc.e04-07-0616. View

Lisanti M, Scherer P, Vidugiriene J, Tang Z, Hermanowski-Vosatka A, Tu Y . Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease. J Cell Biol. 1994; 126(1):111-26. PMC: 2120102. DOI: 10.1083/jcb.126.1.111. View

10.

Ring A, Le Lay S, Pohl J, Verkade P, Stremmel W . Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. Biochim Biophys Acta. 2006; 1761(4):416-23. DOI: 10.1016/j.bbalip.2006.03.016. View

11.

Coburn C, Knapp Jr F, Febbraio M, Beets A, Silverstein R, Abumrad N . Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem. 2000; 275(42):32523-9. DOI: 10.1074/jbc.M003826200. View

12.

Tanaka T, Nakata T, Oka T, Ogawa T, Okamoto F, Kusaka Y . Defect in human myocardial long-chain fatty acid uptake is caused by FAT/CD36 mutations. J Lipid Res. 2001; 42(5):751-9. View

13.

Hames K, Vella A, Kemp B, Jensen M . Free fatty acid uptake in humans with CD36 deficiency. Diabetes. 2014; 63(11):3606-14. PMC: 4207394. DOI: 10.2337/db14-0369. View

14.

Abumrad N, El-Maghrabi M, Amri E, Lopez E, Grimaldi P . Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J Biol Chem. 1993; 268(24):17665-8. View

15.

Xu S, Jay A, Brunaldi K, Huang N, Hamilton J . CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry. 2013; 52(41):7254-61. DOI: 10.1021/bi400914c. View

16.

Resh M . Trafficking and signaling by fatty-acylated and prenylated proteins. Nat Chem Biol. 2006; 2(11):584-90. DOI: 10.1038/nchembio834. View

17.

Linder M, Deschenes R . Palmitoylation: policing protein stability and traffic. Nat Rev Mol Cell Biol. 2006; 8(1):74-84. DOI: 10.1038/nrm2084. View

18.

Fukata Y, Murakami T, Yokoi N, Fukata M . Local Palmitoylation Cycles and Specialized Membrane Domain Organization. Curr Top Membr. 2016; 77:97-141. DOI: 10.1016/bs.ctm.2015.10.003. View

19.

Peng T, Thinon E, Hang H . Proteomic analysis of fatty-acylated proteins. Curr Opin Chem Biol. 2015; 30:77-86. PMC: 4731282. DOI: 10.1016/j.cbpa.2015.11.008. View

20.

Wang J, Hao J, Wang X, Guo H, Sun H, Lai X . DHHC4 and DHHC5 Facilitate Fatty Acid Uptake by Palmitoylating and Targeting CD36 to the Plasma Membrane. Cell Rep. 2019; 26(1):209-221.e5. DOI: 10.1016/j.celrep.2018.12.022. View