Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Science, 2300 Eye Street, N.W., Washington, DC 20037, USA.
State Key Laboratory of Proteomics, National Center for Protein Sciences - Beijing, Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing 102206, China; Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430062, China.
Mol Cell. 2021 May 6;81(9):1890-1904.e7. doi: 10.1016/j.molcel.2021.02.009. Epub 2021 Mar 2.
O-linked β-N-acetyl glucosamine (O-GlcNAc) is attached to proteins under glucose-replete conditions; this posttranslational modification results in molecular and physiological changes that affect cell fate. Here we show that posttranslational modification of serine/arginine-rich protein kinase 2 (SRPK2) by O-GlcNAc regulates de novo lipogenesis by regulating pre-mRNA splicing. We found that O-GlcNAc transferase O-GlcNAcylated SRPK2 at a nuclear localization signal (NLS), which triggers binding of SRPK2 to importin α. Consequently, O-GlcNAcylated SRPK2 was imported into the nucleus, where it phosphorylated serine/arginine-rich proteins and promoted splicing of lipogenic pre-mRNAs. We determined that protein nuclear import by O-GlcNAcylation-dependent binding of cargo protein to importin α might be a general mechanism in cells. This work reveals a role of O-GlcNAc in posttranscriptional regulation of de novo lipogenesis, and our findings indicate that importin α is a "reader" of an O-GlcNAcylated NLS.
O-连接的β-N-乙酰氨基葡萄糖（O-GlcNAc）在葡萄糖充足的条件下连接到蛋白质上；这种翻译后修饰导致分子和生理变化，影响细胞命运。在这里，我们表明，通过 O-GlcNAc 对丝氨酸/精氨酸丰富的蛋白激酶 2（SRPK2）的翻译后修饰，通过调节前体 mRNA 的剪接来调节从头脂肪生成。我们发现 O-GlcNAc 转移酶 O-GlcNAc 化 SRPK2 的核定位信号（NLS），这触发了 SRPK2 与导入蛋白 α的结合。因此，O-GlcNAc 化的 SRPK2 被导入细胞核，在那里它磷酸化丝氨酸/精氨酸丰富的蛋白并促进脂肪生成前体 mRNA 的剪接。我们确定了 O-GlcNAc 依赖性货物蛋白与导入蛋白 α 的结合对蛋白质核输入可能是细胞中的一种普遍机制。这项工作揭示了 O-GlcNAc 在从头脂肪生成的转录后调节中的作用，我们的发现表明导入蛋白 α 是 O-GlcNAc 化 NLS 的“阅读器”。
