Department of Molecular, Cell and Cancer Biology and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, China.
Cell Rep. 2018 Mar 13;22(11):2860-2872. doi: 10.1016/j.celrep.2018.02.057.
Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function. Moreover, this sumoylation event primes Prdm16 to be further stabilized by methyltransferase Ehmt1. Heterozygous Cbx4-knockout mice develop metabolic phenotypes resembling those of Prdm16-knockout mice. Furthermore, fat-specific Cbx4 knockdown and overexpression produce remarkable, opposite effects on white fat remodeling. Our results identify a modifying enzyme for Prdm16, and they demonstrate a central role of Cbx4 in the control of Prdm16 stability and white fat browning.
转录共激活因子 Prdm16 控制棕色脂肪发育和白色脂肪棕色化，但这种产热功能如何在翻译后被调节还知之甚少。在这里，我们报告说，多梳蛋白 Cbx4 是 Prdm16 的 SUMO E3 连接酶，Cbx4 介导的 Prdm16 SUMO 化对于产热基因的表达是必需的。Cbx4 在棕色脂肪中表达丰富，并在急性冷暴露下在脂肪组织中被诱导。Cbx4 对 Prdm16 的赖氨酸 917 进行 SUMO 化会阻止其泛素化介导的降解，从而增加其稳定性和产热功能。此外，该 SUMO 化事件使 Prdm16 更容易被甲基转移酶 Ehmt1 进一步稳定。杂合 Cbx4 敲除小鼠表现出类似于 Prdm16 敲除小鼠的代谢表型。此外，脂肪特异性 Cbx4 敲低和过表达对白色脂肪重塑产生显著的相反效果。我们的研究结果确定了 Prdm16 的一种修饰酶，并证明了 Cbx4 在控制 Prdm16 稳定性和白色脂肪棕色化中的核心作用。
