Department of Life Science (BK21 Program), College of Natural Sciences, Chung-Ang University, Seoul, South Korea.
Mol Cell Biol. 2012 May;32(9):1720-32. doi: 10.1128/MCB.06440-11. Epub 2012 Feb 21.
Neural retina leucine zipper (Nrl), a key basic motif leucine zipper (bZIP) transcription factor, modulates rod photoreceptor differentiation by activating rod-specific target genes. In searching for factors that might couple with Nrl to modulate its transcriptional activity through posttranslational modification, we observed the novel interactions of Nrl with c-Jun N-terminal kinase 1 (JNK1) and HIV Tat-interacting protein 60 (Tip60). JNK1 directly interacted with and phosphorylated Nrl at serine 50, which enhanced Nrl transcriptional activity on the rhodopsin and Ppp2r5c promoters. Use of an inactive JNK1 mutant or treatment with a JNK inhibitor (SP600125) significantly reduced JNK1-mediated phosphorylation and transcriptional activity of Nrl in cultured retinal explants. We also found that Nrl activated rhodopsin and Ppp2r5c transcription by recruiting Tip60 to promote histone H3/H4 acetylation. The binding affinity of phospho-Nrl for Tip60 was significantly greater than that of the unphosphorylated Nrl. Thus, the histone acetyltransferase-containing Tip60 behaved as a coactivator in the Nrl-dependent transcriptional regulation of the rhodopsin and Ppp2r5c genes in the developing mouse retina. A transcriptional network of interactive proteins, including Nrl, JNK1, and Tip60, may be required to precisely control spatiotemporal photoreceptor-specific gene expression during retinal development.
神经视网膜亮氨酸拉链（Nrl）是一种关键的基本亮氨酸拉链（bZIP）转录因子，通过激活 rod 特异性靶基因来调节 rod 光感受器分化。在寻找可能与 Nrl 相互作用的因子，通过翻译后修饰来调节其转录活性时，我们观察到 Nrl 与 c-Jun N 端激酶 1（JNK1）和 HIV Tat 相互作用蛋白 60（Tip60）的新相互作用。JNK1 直接与 Nrl 相互作用并使其丝氨酸 50 磷酸化，这增强了 Nrl 在视紫红质和 Ppp2r5c 启动子上的转录活性。使用无活性的 JNK1 突变体或 JNK 抑制剂（SP600125）处理可显著降低 JNK1 介导的 Nrl 在培养的视网膜外植体中的磷酸化和转录活性。我们还发现 Nrl 通过募集 Tip60 激活视紫红质和 Ppp2r5c 转录，从而促进组蛋白 H3/H4 乙酰化。磷酸化 Nrl 与 Tip60 的结合亲和力明显大于非磷酸化 Nrl。因此，含有组蛋白乙酰转移酶的 Tip60 在 Nrl 依赖性的视紫红质和 Ppp2r5c 基因转录调节中作为共激活因子发挥作用在发育中的小鼠视网膜中。包括 Nrl、JNK1 和 Tip60 在内的相互作用蛋白的转录网络可能需要精确控制视网膜发育过程中时空特异性光感受器基因的表达。
