Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity.
Phosphorylation-facilitated sumoylation of MEF2C negatively regulates its transcriptional activity.
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DOI：
10.1186/1471-2091-7-5
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发表时间：
2006-02-14
期刊：
影响因子：
--
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Kang J;Gocke CB;Yu H
Sumoylation 已成为转录因子和辅助因子的重要翻译后调节机制。许多转录因子的苏酰化会抑制它们的转录活性。转录因子的肌细胞增强因子 2 (MEF2) 家族在肌生成过程中调节基因表达中发挥着重要作用，并且最近已被证明被苏酰化。与之前的报道一致，我们表明 MEF2C 在 K391 处的 SUMO 化会抑制其转录活性。 MEF2C 的苏酰化不会阻断其 DNA 结合活性。含有 K391 的 MEF2C C 末端小片段（称为 delta-N2-MEF2C）可被有效地苏酰化，当靶向 DNA 时，会抑制邻近启动子处的转录。由于 delta-N2-MEF2C 缺乏 II 类组蛋白脱乙酰酶 (HDAC) 的结合位点，因此该结果表明 MEF2C 的苏酰化可能有助于招募除这些 HDAC 之外的转录阻遏蛋白。有趣的是，我们发现 MEF2C 中 S396 的磷酸化（靠近主要苏酰化位点（K391）且已知在体内磷酸化的残基）在体外增强了 delta-N2-MEF2C 的苏酰化。 S396A 突变减少了 MEF2C 体内的 sumoylation，并增强了 MEF2C 在报告基因检测中的转录活性。我们认为 MEF2C 在 S396 处的磷酸化促进了其在 K391 处的苏酰化，从而招募尚未识别的共阻遏物来抑制转录。我们的研究进一步表明，在+5位置含有磷酸化丝氨酸或酸性残基的苏酰化基序可能会更有效地苏酰化。
Sumoylation has emerged as an important posttranslational regulatory mechanism for transcription factors and cofactors. Sumoylation of many transcription factors represses their transcriptional activities. The myocyte enhancer factor 2 (MEF2) family of transcription factors plays an important role in regulating gene expression during myogenesis and has been recently shown to be sumoylated. Consistent with earlier reports, we show that sumoylation of MEF2C at K391 inhibits its transcriptional activity. Sumoylation of MEF2C does not block its DNA-binding activity. A small C-terminal fragment of MEF2C containing K391, referred to as delta-N2-MEF2C, is efficiently sumoylated and, when targeted to DNA, represses transcription at neighbouring promoters. Because delta-N2-MEF2C lacks the binding site for class II histone deacetylases (HDACs), this result suggests that sumoylation of MEF2C may help to recruit transcriptional repressors other than these HDACs. Intriguingly, we show that phosphorylation of S396 in MEF2C, a residue in close proximity to the major sumoylation site (K391) and known to be phosphorylated in vivo, enhances sumoylation of delta- N2-MEF2C in vitro. The S396A mutation reduces sumoylation of MEF2C in vivo and enhances the transcription activity of MEF2C in reporter assays. We propose that phosphorylation of MEF2C at S396 facilitates its sumoylation at K391, which in turn recruits yet unidentified co-repressors to inhibit transcription. Our studies further suggest that sumoylation motifs containing a phosphorylated serine or an acidic residue at the +5 position might be more efficiently sumoylated.
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