Faculty of Medical Laboratory Science, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai 200025, China; Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai 200025, China; Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Cell Rep. 2019 Aug 20;28(8):2004-2011.e4. doi: 10.1016/j.celrep.2019.07.083.
Brown adipose tissue (BAT) is a thermogenic organ that maintains body temperature and energy homeostasis. Transcriptional regulation plays an important role in the program of brown adipogenesis. However, it remains unclear how the transcriptional events are controlled in this program. In this study, we analyze an SENP2 BAT conditional knockout mouse model and find that SENP2-mediated de-SUMOylation is essential for BAT development. SENP2 catalyzes de-SUMOylation of cAMP response element-binding protein (CREB) to suppress Necdin expression, which induces brown adipocyte differentiation and brown adipogenesis. Mechanistically, we find that SUMOylation enhances CREB interaction with serine/threonine protein phosphatase 2A (PP2A) to de-phosphorylate CREB, which activates Necdin transcription. SENP2 deficiency enhances the expression of Necdin to inhibit brown adipocyte differentiation. Therefore, we reveal a crucial role of SENP2-mediated de-SUMOylation of CREB in suppression of Necdin expression during brown adipose development and brown adipogenesis.
棕色脂肪组织（BAT）是一种产热器官，可维持体温和能量稳态。转录调控在棕色脂肪生成的程序中起着重要作用。然而，在这个程序中，转录事件是如何被控制的仍不清楚。在这项研究中，我们分析了 SENP2BAT 条件性敲除小鼠模型，发现 SENP2 介导的去 SUMO 化对于 BAT 发育是必不可少的。SENP2 催化 cAMP 反应元件结合蛋白（CREB）的去 SUMO 化，以抑制 Necdin 的表达，从而诱导棕色脂肪细胞分化和棕色脂肪生成。从机制上讲，我们发现 SUMO 化增强了 CREB 与丝氨酸/苏氨酸蛋白磷酸酶 2A（PP2A）的相互作用，以去磷酸化 CREB，从而激活 Necdin 转录。SENP2 的缺乏会增强 Necdin 的表达，从而抑制棕色脂肪细胞的分化。因此，我们揭示了 SENP2 介导的 CREB 去 SUMO 化在棕色脂肪发育和棕色脂肪生成过程中抑制 Necdin 表达中的关键作用。
