Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway
Crosstalk between O-GlcNAcylation and proteolytic cleavage regulates the host cell factor-1 maturation pathway
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DOI：
10.1073/pnas.1013822108
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发表时间：
2011-02-15
影响因子：
11.1
通讯作者：
Affar, El Bachir
中科院分区：
文献类型：
--
作者：
Daou, Salima;Mashtalir, Nazar;Affar, El Bachir
宿主细胞因子1（HCF-1）在许多生理过程中对基因表达起着重要的调控作用。HCF-1首先作为前体合成，随后在称为蛋白水解加工结构域（PPD）的大的中间区域内特异性蛋白水解切割。尽管其潜在的机制仍然是个谜，但HCF-1的蛋白水解调节其转录活性，并且对细胞周期进展很重要。在这里，我们报告说，HCF-1蛋白水解是一个受调节的过程。我们证明，大部分的信号酶O-连接-N-乙酰葡糖胺基转移酶（OGT）与HCF-1复合，这种相互作用是必不可少的HCF-1切割。此外，HCF-1反过来又是稳定细胞核中OGT所必需的。我们提供的证据表明，OGT通过与HCF-1 PPD相互作用和O-GlcNAc化调节HCF-1切割。相反，尽管OGT也与HCF-1氨基末端亚基中的碱性结构域相互作用，但蛋白水解既不需要该区域的相互作用也不需要该区域的O-GlcNAc化。此外，我们发现OGT介导的HCF-1调节影响单纯疱疹病毒即早期基因的表达，即HCF-1在病毒感染开始时的靶点。这些数据共同表明，HCF-1的O-GlcNAc酰化是其蛋白水解加工的信号，并揭示了这些翻译后修饰之间的独特串扰。此外，OGT与多个HCF-1结构域的相互作用可能表明OGT具有与HCF-1相关的几种功能。
Host Cell Factor 1 (HCF-1) plays critical roles in regulating gene expression in a plethora of physiological processes. HCF-1 is first synthesized as a precursor, and subsequently specifically proteolytically cleaved within a large middle region termed the proteolytic processing domain (PPD). Although the underlying mechanism remains enigmatic, proteolysis of HCF-1 regulates its transcriptional activity and is important for cell cycle progression. Here we report that HCF-1 proteolysis is a regulated process. We demonstrate that a large proportion of the signaling enzyme O-linked-N-acetylglucosaminyl transferase (OGT) is complexed with HCF-1 and this interaction is essential for HCF-1 cleavage. Moreover, HCF-1 is, in turn, required for stabilizing OGT in the nucleus. We provide evidence indicating that OGT regulates HCF-1 cleavage via interaction with and O-GlcNAcylation of the HCF-1 PPD. In contrast, although OGT also interacts with the basic domain in the HCF-1 amino-terminal subunit, neither the interaction nor the O-GlcNAcylation of this region are required for proteolysis. Moreover, we show that OGT-mediated modulation of HCF-1 impacts the expression of the herpes simplex virus immediate-early genes, targets of HCF-1 during the initiation of viral infection. Together the data indicate that O-GlcNAcylation of HCF-1 is a signal for its proteolytic processing and reveal a unique crosstalk between these posttranslational modifications. Additionally, interactions of OGT with multiple HCF-1 domains may indicate that OGT has several functions in association with HCF-1.