Department of Life Sciences, Shiv Nadar University, Greater Noida, India.
Sci Rep. 2017 Jun 16;7(1):3635. doi: 10.1038/s41598-017-03783-w.
PXR is a member of nuclear receptor superfamily and a well-characterized mediator of xenobiotic metabolism. The classical mode of PXR activation involves its binding to appropriate ligand and subsequent heterodimerization with its partner RXR. However, various factors such as post-translational modifications and crosstalk with different cellular factors may also regulate the functional dynamics and behavior of PXR. In the present study, we have identified that TIP60, an essential lysine acetyltransferase protein interacts with unliganded PXR and together this complex promotes cell migration & adhesion. TIP60 utilizes its NR Box to interact with LBD region of PXR and acetylates PXR at lysine 170 to induce its intranuclear reorganization. Also, RXR is not required for TIP60-PXR complex formation and this complex does not induce ligand-dependent PXR target gene transactivation. Interestingly, we observed that PXR augments the catalytic activity of TIP60 for histones. This is the first report demonstrating the exclusive interaction of TIP60 with PXR and uncovers a potential role for the TIP60-PXR complex in cell migration and adhesion.
PXR 是核受体超家族的成员，也是一种经过充分研究的外源物质代谢调节剂。PXR 的经典激活模式涉及与适当配体结合，随后与伴侣 RXR 形成异二聚体。然而，各种因素，如翻译后修饰和与不同细胞因子的串扰，也可能调节 PXR 的功能动态和行为。在本研究中，我们已经确定 TIP60，一种必需的赖氨酸乙酰转移酶蛋白，与未配体结合的 PXR 相互作用，并且这个复合物促进细胞迁移和黏附。TIP60 利用其 NR 盒与 PXR 的 LBD 区域相互作用，并在赖氨酸 170 处乙酰化 PXR，以诱导其核内重排。此外，RXR 不是 TIP60-PXR 复合物形成所必需的，并且这个复合物不会诱导配体依赖性 PXR 靶基因转录激活。有趣的是，我们观察到 PXR 增强了 TIP60 对组蛋白的催化活性。这是首次报道 TIP60 与 PXR 的特异性相互作用，并揭示了 TIP60-PXR 复合物在外源物质代谢调节剂在细胞迁移和黏附中的潜在作用。
