Lens epithelium-derived growth factor deSumoylation by Sumo-specific protease-1 regulates its transcriptional activation of small heat shock protein and the cellular response.
Lens epithelium-derived growth factor deSumoylation by Sumo-specific protease-1 regulates its transcriptional activation of small heat shock protein and the cellular response.
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DOI：
10.1111/j.1742-4658.2012.08686.x
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发表时间：
2012-09
期刊：
影响因子：
--
通讯作者：
Singh DP
中科院分区：
文献类型：
--
作者：
Ishihara K;Fatma N;Bhargavan B;Chhunchha B;Kubo E;Dey S;Takamura Y;Kumar A;Singh DP
透镜上皮源性生长因子（LEDGF）是一种广泛表达的核蛋白，通过与DNA和蛋白质相互作用发挥作用，并参与多种细胞功能。尽管其重要性，但调节天然存在的LEDGF活性的机制尚未确定。在这里，我们报告，LEDGF是组成性的Sumoylated，和动态调节机制（S），Sumoylation和deSumoylation作为一个分子开关，在调节DNA结合和转录活性的LEDGF的功能后果。利用生物信息学分析结合体外和体内Sumoylation分析，我们发现LEDGF的赖氨酸（K）364被Sumoylated，抑制其转录活性。相反，K364突变为精氨酸（R）或通过Senp-1（一种核去类小泛素化酶）进行去类小泛素化，增强了LEDGF的反式激活能力及其细胞丰度。这种增强与LEDGF的DNA结合活性和小热休克蛋白（Hsps）转录的增加直接相关，而在过表达Sumo 1的细胞中，这一过程被逆转。有趣的是，与野生型LEDGF蛋白相比，表达Sumoylation缺陷型pEGFP-K364 R蛋白的细胞显示出增加的细胞存活。这些发现提供了对LEDGF在Sumoylation依赖性转录控制中的调节和调节功能的见解，这可能是修改细胞生理以维持细胞稳态所必需的。这些研究也为翻译后修饰在控制LEDGF功能中的重要作用提供了新的证据。
Lens epithelium-derived growth factor (LEDGF), a ubiquitously expressed nuclear protein, acts by interacting with DNA and protein and is involved in widely varying cellular functions. Despite its importance, the mechanism(s) that regulate naturally occurring LEDGF activity are unidentified. Here we report that LEDGF is constitutively Sumoylated, and that the dynamical regulatory mechanism(s), Sumoylation and deSumoylation act as a molecular switch in modulating DNA binding and transcriptional activity of LEDGF with the functional consequences. Using bioinformatics analysis coupled with in vitro and in vivo Sumoylation assays, we found that lysine (K) 364 of LEDGF was Sumoylated, repressing its transcriptional activity. Conversely, mutation of K364 to arginine (R) or deSumoylation by Senp-1, a nuclear deSumoylase, enhanced the transactivation capacity of LEDGF and its cellular abundance. The enhancements were directly correlated with an increase in LEDGF’s DNA binding activity and small heat shock protein (Hsps) transcription, while the process was reversed in cells overexpressing Sumo1. Interestingly, cells expressing Sumoylation-deficient pEGFP-K364R protein showed increased cellular survival compared with the wild-type LEDGF protein. The findings provide insights into regulation and regulatory functions of LEDGF in Sumoylation-dependent transcriptional control that may be essential for modifying the physiology of cells to maintain cellular homeostasis. These studies also provide new evidence of the important role of post-translational modification in controlling LEDGF function.
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