Environmental cues such as nutrients alter cellular behaviors by acting on a wide array of molecular sensors inside cells. Of emerging interest is the link observed between effects of dietary sugars on cancer proliferation. Here, we identify the requirements of hexosamine biosynthetic pathway (HBP) and O-GlcNAc transferase (OGT) for Drosophila homeodomain-interacting protein kinase (Hipk)-induced growth abnormalities in response to a high sugar diet. On a normal diet, OGT is both necessary and sufficient for inducing Hipk-mediated tumor-like growth. We further show that OGT maintains Hipk protein stability by blocking its proteasomal degradation and that Hipk is O-GlcNAcylated by OGT. In mammalian cells, human HIPK2 proteins accumulate posttranscriptionally upon OGT overexpression. Mass spectrometry analyses reveal that HIPK2 is at least O-GlcNAc modified at S852, T1009, and S1147 residues. Mutations of these residues reduce HIPK2 O-GlcNAcylation and stability. Together, our data demonstrate a conserved role of OGT in positively regulating the protein stability of HIPKs (fly Hipk and human HIPK2), which likely permits the nutritional responsiveness of HIPKs.

中文翻译：

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营养传感器OGT调节果蝇中的Hipk稳定性和致瘤样活性。

营养物质等环境线索通过作用于细胞内部的多种分子传感器来改变细胞行为。引起人们关注的是饮食糖对癌症扩散的影响之间的联系。在这里，我们确定了对高糖饮食响应果蝇同源域相互作用蛋白激酶（Hipk）的果蝇的六胺生物合成途径（HBP）和O-GlcNAc转移酶（OGT）的要求。在正常饮食中，OGT对于诱导Hipk介导的肿瘤样生长既必要又充分。我们进一步表明，OGT通过阻止其蛋白酶体降解来维持Hipk蛋白质的稳定性，并且Hipk被OGT修饰为O-GlcNAcylated。在哺乳动物细胞中，人类HIPK2蛋白在OGT过表达时在转录后积累。质谱分析显示，HIPK2至少在S852，T1009和S1147残基处被O-GlcNAc修饰。这些残基的突变降低了HIPK2 O-GlcNAcylation和稳定性。在一起，我们的数据表明OGT在积极调节HIPKs（果蝇Hipk和人类HIPK2）的蛋白质稳定性中的保守作用，这很可能允许HIPKs的营养响应。