The SCF ubiquitin ligase Slimb controls Nerfin-1 turnover in Drosophila.
The SCF ubiquitin ligase Slimb controls Nerfin-1 turnover in Drosophila.
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DOI：
10.1016/j.bbrc.2017.11.090
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发表时间：
2018
影响因子：
3.1
通讯作者：
Xiaohui Lin;Feng Wang;Yuanpei Li;Chaojun Zhai;Guiping Wang;Xiaoting Zhang;Yang Gao;Tao Yi;Dan Sun;Shian Wu
中科院分区：
文献类型：
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作者：
Xiaohui Lin;Feng Wang;Yuanpei Li;Chaojun Zhai;Guiping Wang;Xiaoting Zhang;Yang Gao;Tao Yi;Dan Sun;Shian Wu
C2H2型锌指转录因子Nerfin-1在果蝇神经系统中主要表达，在轴突早期引导决策和阻止神经元去分化中起重要作用。近年来，越来越多的报道表明INSM1（哺乳动物中与nerfin-1同源的基因）是判断神经内分泌肿瘤预后的有用标记物。Nerfin-1的动态表达在转录后受到多种microrna的调控；然而，其翻译后调控尚不清楚。在这里，我们发现Nerfin-1的蛋白质周转是由Slimb调节的，Slimb是SCFSlimbubiquitin连接酶复合物的底物接头。从机制上讲，slim与Nerfin-1相关，并促进其在果蝇S2R+细胞中的泛素化和降解。此外，我们确定了Nerfin-1的c端一半（Nerfin-1CT）是其与slim结合所必需的。遗传上位性分析表明，slam错表达可拮抗nerfin - 1ctins，而敲除可增强其活性。我们的数据揭示了在翻译后水平上理解Nerfin-1转换的潜在机制的新联系，并通过操纵sllimb和Nerfin-1的活性为动物发育和疾病治疗提供了有用的见解。
The C2H2 type zinc-finger transcription factor Nerfin-1 expresses dominantly inDrosophilanervous system and plays an important role in early axon guidance decisions and preventing neurons dedifferentiation. Recently, increasing reports indicated that INSM1 (homologue to nerfin-1 in mammals) is a useful marker for prognosis of neuroendocrine tumors. The dynamic expression of Nerfin-1 is regulated post-transcriptionally by multiple microRNAs; however, its post-translational regulation is still unclear. Here we showed that the protein turnover of Nerfin-1 is regulated by Slimb, the substrate adaptor of SCFSlimbubiquitin ligase complex. Mechanistically, Slimb associates with Nerfin-1 and promotes it ubiquitination and degradation inDrosophila S2R+cells. Furthermore, we determined that the C-terminal half of Nerfin-1 (Nerfin-1CT) is required for its binding to Slimb. Genetic epistasis assays showed that Slimb misexpression antagonizes, while knock-down enhances the activity of Nerfin-1CTinDrosophilaeyes. Our data revealed a new link to understand the underlying mechanism for Nerfin-1 turnover in post-translational level, and provided useful insights in animal development and disease treatment by manipulating the activity of Slimb and Nerfin-1.