Small Ubiquitin-like Modifier (SUMO) Modification Inhibits GLI2 Protein Transcriptional Activity in Vitro and in Vivo
Small Ubiquitin-like Modifier (SUMO) Modification Inhibits GLI2 Protein Transcriptional Activity in Vitro and in Vivo
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DOI：
10.1074/jbc.m112.359299
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发表时间：
2012-06-08
影响因子：
4.8
通讯作者：
Wang, Baolin
中科院分区：
文献类型：
--
作者：
Han, Lizhang;Pan, Yong;Wang, Baolin
Gli转录因子是Hedgehog（Hh）信号通路的关键下游介质。Gli转录因子的活性如何受上游Hh信号传导事件和蛋白质修饰的调控尚不完全清楚。在这里，我们表明，GLI2是由小泛素样修饰剂（SUMO）在细胞中的赖氨酸残基630和716共轭。GLI2类小泛素化的水平通过通常被蛋白激酶A（PKA）磷酸化的六个丝氨酸残基中的突变或HH的刺激而降低。这表明PKA磷酸化增强了GLI2类小泛素化，而HH信号抑制它。此外，这两个赖氨酸突变为精氨酸残基显着增加GLI2的转录活性在基于细胞的报告分析。GLI2基因座中的相同突变也导致小鼠中GLI2活性的增加。有趣的是，GLI2可以与HDAC5（组蛋白脱乙酰酶5）相互作用，但GLI2突变体不能。总之，我们的结果表明，SUMO修饰抑制GLI2转录活性招募HDAC5。
The Gli transcription factors are key downstream mediators of the Hedgehog (Hh) signaling pathway. How the activities of Gli transcription factors are regulated by upstream Hh signaling events and protein modifications are not fully understood. Here we show that GLI2 is conjugated by small ubiquitin-like modifier (SUMO) at lysine residues 630 and 716 in the cell. The level of GLI2 sumoylation is reduced by either mutations in six serine residues that are normally phosphorylated by protein kinase A (PKA) or stimulation by HH. This suggests that PKA phosphorylation enhances GLI2 sumoylation, whereas HH signaling inhibits it. In addition, mutation of these two lysines into arginine residues significantly increases GLI2 transcriptional activity in a cell-based reporter assay. The same mutations in the GLI2 locus also result in an increase in GLI2 activity in the mouse. Interestingly, GLI2 can interact with HDAC5 (histone deacetylase 5), but the GLI2 mutant cannot. Taken together, our results suggest that SUMO modification inhibits GLI2 transcriptional activity by recruiting HDAC5.