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Palmitoylation maintains plasma membrane localization of glucose transporter GLUT1 to promote glycolysis and malignance of glioblastoma

Updated: 2021-10-08

Glucose is the major source of energy in human cells. One molecule of glucose is converted to 2 molecules of pyruvate, and generating 2 molecules of ATP during glycolysis in mammalian cells. Pyruvate produced from glycolysis is either transported into mitochondria to be further converted to carbon dioxide and water through the tricarboxylic acid (TCA) cycle coupled with the electron transport chain pathway, or reduced to lactate, a secretory metabolite, by lactate dehydrogenase in the cytosol. In 1924, German physiologist Otto Warburg proposed that tumor cells, but not healthy cells, produce ATP by glycolysis rather than TCA cycle and have high rate of lactate secretion, even when oxygen is available, this metabolic phenotype was named Warburg effect. Recently, many studies support that Warburg effect contributes to rapid proliferation, metastasis, and chemo-resistance of cancers. The uptake of glucose is facilitated by glucose transporters, which family contains more than 10 members, among them GLUT1, a most ubiquitously expressed glucose transporter, plays an essential role for glucose supply in many tissues. Of note, cancer cells have a high rate of glucose-dependent aerobic glycolysis, thereby keeping high levels of cellular glucose uptake is indispensable to support the rapid proliferation of cancer cells.


Palmitoylation, a posttranslational modification formed by connecting the carboxyl group of palmitic acid to the sulfhydryl group of cysteine in proteins, is catalyzed by palmitoyl transferases in eukaryotic cells. Twenty-three palmitoyl transferases have been identified in mammalian cells and characterized to regulate membrane localization, inter-membrane translocation, interaction, and stability of intracellular proteins. Notably, palmitic acid, a long chain fatty acid which possessing hydrophobic property, is able to insert into lipid bilayer membranes, leading to membrane localization of palmitoylated proteins. Therefore, palmitoylation may regulate the functions of plasma membrane (PM)-localized proteins, such as metabolite transporters, cytokine receptor, and G-protein-coupled receptors.


Recently, Dr. LI Xinjian's group at the Institute of Biophysics, Chinese Academy of Sciences, reports that GLUT1 is palmitoylated at Cys207, and S-palmitoylation is required for maintaining GLUT1 PM localization. Mechanistically, DHHC9 is identified as the palmitoyl transferase responsible for this critical posttranslational modification. Knockout of DHHC9 or mutation of GLUT1 Cys207 to serine abrogates palmitoylation and PM distribution of GLUT1, and impairs glycolysis, cell proliferation, and glioblastoma (GBM) tumorigenesis. These findings demonstrate that GBM cells have increased dependence on DHHC9-mediated GLUT1 S-palmitoylation, unlike normal astrocytes which primarily depend on other mechanisms to maintain their glycolysis, highlighting that DHHC9 could be a potential target for cancer cell specific inhibition of glycolysis. In addition, DHHC9 expression positively correlates with GLUT1 PM localization in GBM specimens and indicates a poor prognosis in GBM patients.


Figure. A mechanism of S-palmitoylated GLUT1-dependent glycolysis. GLUT1 Cys207 palmitoylation catalyzed by DHHC9 resulted in PM localization of GLUT1, leading to enhanced uptake of glucose, thereby promoting glycolysis, cell growth, and GBM tumorigenesis.


This work was supported by Key Program of the Chinese Academy of Sciences (Grant No. KJZD-SW-L05 to LI Xinjian); the National Natural Science Foundation of China (Grant No. 82073060 to LI Xinjian); the National Key R&D Program of China (Grant No. 2020YFC2002700 to LI Xinjian); and the National Science Foundation for Young Scientists of China (Grant No. 82003032 to Z.Z.).


Article link:https://www.nature.com/articles/s41467-021-26180-4


Contact: LI Xinjian

Institute of Biophysics, Chinese Academy of Sciences

Beijing 100101, China

Email: lixinjian@ibp.ac.cn


(Reported by Dr. LI Xinjian's group)


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