DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis.
DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis.
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DHHC 9介导的GLUT 1 S-棕榈酰化促进胶质母细胞瘤糖酵解和肿瘤发生
DOI：
10.1038/s41467-021-26180-4
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发表时间：
2021-10-07
影响因子：
16.6
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Zhang Z;Li X;Yang F;Chen C;Liu P;Ren Y;Sun P;Wang Z;You Y;Zeng YX;Li X
葡萄糖转运蛋白GLUT1是一种跨膜蛋白，负责通过促进扩散将葡萄糖摄取到许多组织的细胞中。质膜（PM）定位对GLUT1摄取葡萄糖至关重要。然而，GLUT1 PM定位的机制仍然是个谜。我们发现GLUT1在Cys207位点发生棕榈酰化，而s -棕榈酰化是维持GLUT1 PM定位所必需的。此外，我们确定DHHC9是负责这一关键翻译后修饰的棕榈酰转移酶。敲除DHHC9或GLUT1 Cys207突变为丝氨酸，可消除GLUT1的棕榈酰化和PM分布，并损害糖酵解、细胞增殖和胶质母细胞瘤（GBM）的肿瘤发生。此外，在GBM标本中，DHHC9表达与GLUT1 PM定位呈正相关，提示GBM患者预后较差。这些发现强调dhhc9介导的GLUT1 s -棕榈酰化对GBM肿瘤发生过程中的葡萄糖供应至关重要。葡萄糖转运蛋白GLUT1在多种癌症中上调，并可能促进肿瘤进展，但其潜在机制尚不清楚。在这里，作者表明dhhc9介导的GLUT1棕榈酰化在Cys207位点对GLUT1的质膜定位和胶质母细胞瘤细胞的肿瘤发生至关重要。
Glucose transporter GLUT1 is a transmembrane protein responsible for the uptake of glucose into the cells of many tissues through facilitative diffusion. Plasma membrane (PM) localization is essential for glucose uptake by GLUT1. However, the mechanism underlying GLUT1 PM localization remains enigmatic. We find that GLUT1 is palmitoylated at Cys207, and S-palmitoylation is required for maintaining GLUT1 PM localization. Furthermore, we identify DHHC9 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. In addition, DHHC9 expression positively correlates with GLUT1 PM localization in GBM specimens and indicates a poor prognosis in GBM patients. These findings underscore that DHHC9-mediated GLUT1 S-palmitoylation is critical for glucose supply during GBM tumorigenesis. The glucose transporter GLUT1 is upregulated in multiple cancers and may contribute to tumour progression, but the underlying mechanisms are poorly understood. Here, the authors show that DHHC9-mediated GLUT1 palmitoylation at Cys207 is crucial for plasma membrane localisation of GLUT1 and for tumourigenesis in glioblastoma cells.
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