The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation.
The Binding of CSL Proteins to Either Co-Activators or Co-Repressors Protects from Proteasomal Degradation Induced by MAPK-Dependent Phosphorylation.
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DOI：
10.3390/ijms232012336
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发表时间：
2022-10-15
影响因子：
5.6
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中科院分区：
文献类型：
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Notch的主要作用是指定细胞身份，从而细胞对Notch信号活性的微小变化做出反应。因此，Notch组分的剂量对于调节至关重要。Notch信号转导的中心是CSL蛋白：与各自的辅因子一起，它们介导Notch靶基因的激活或沉默。CSL蛋白在物种之间就序列和结构而言极其相似。我们注意到，果蝇同源物无毛抑制因子（Su（H））在转录复合物中是稳定的。使用特定的转基因果蝇品系和HeLa RBPJKO细胞，我们提供的证据表明，如果不通过与辅阻遏物hairless或辅激活剂Notch结合来保护，Su（H）会受到蛋白酶体降解，半衰期约为2小时。此外，Su（H）稳定性受MAPK依赖性磷酸化控制，与人细胞中RBPJ的早期数据相匹配。然而，同源鼠和人RBPJ蛋白在我们的系统中很大程度上对降解具有抗性。突变假定的蛋白质接触位点，然而，敏感RBPJ蛋白水解。总体而言，我们的数据突出了跨物种CSL蛋白稳定性调节的相似性，并暗示CSL蛋白的周转可能是直接在转录水平调节Notch信号输出的保守手段。
The primary role of Notch is to specify cellular identities, whereby the cells respond to amazingly small changes in Notch signalling activity. Hence, dosage of Notch components is crucial to regulation. Central to Notch signal transduction are CSL proteins: together with respective cofactors, they mediate the activation or the silencing of Notch target genes. CSL proteins are extremely similar amongst species regarding sequence and structure. We noticed that the fly homologue suppressor of hairless (Su(H)) is stabilised in transcription complexes. Using specific transgenic fly lines and HeLa RBPJKO cells we provide evidence that Su(H) is subjected to proteasomal degradation with a half-life of about two hours if not protected by binding to co-repressor hairless or co-activator Notch. Moreover, Su(H) stability is controlled by MAPK-dependent phosphorylation, matching earlier data for RBPJ in human cells. The homologous murine and human RBPJ proteins, however, are largely resistant to degradation in our system. Mutating presumptive protein contact sites, however, sensitised RBPJ for proteolysis. Overall, our data highlight the similarities in the regulation of CSL protein stability across species and imply that turnover of CSL proteins may be a conserved means of regulating Notch signalling output directly at the level of transcription.
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