Department of Biosciences and Nutrition, Halsovagen 7-9, Karolinska Institutet, 141 86 Stockholm, Sweden.
FASEB J. 2010 Jul;24(7):2396-404. doi: 10.1096/fj.09-149401. Epub 2010 Mar 4.
The Mastermindlike (MAML) family, comprising human MAML1, MAML2, and MAML3, are transcriptional regulators in Notch signaling. MAML proteins contain two consensus sites for SUMOylation at Lysine217 and Lysine299 that are conserved in humans, mice, and Xenopus. In this report, we show that MAML1 is SUMOylated at both sites. The E2-conjugating enzyme UBC9 is essential for MAML1 SUMOylation, and the E3 ligase PIAS1 stimulates this activity. Mutation of the lysines abolishes SUMOylation of MAML1 and strongly increases MAML1-activated transcription in cell culture assays. The protease SENP1 reverses SUMOylation of MAML1 and potentiates the transcription factor activity of MAML1. Furthermore, SUMOylation enhances MAML1 interaction with HDAC7, which decreases MAML1 transcriptional activity. Taken together, our data indicate that SUMOylation of MAML1 is a mechanism for repressing MAML1 activity by influencing its interaction with HDAC7.
主谋样（MAML）家族，包括人类 MAML1、MAML2 和 MAML3，是 Notch 信号转导中的转录调节剂。MAML 蛋白包含两个 SUMO 化赖氨酸 217 和赖氨酸 299 的共识位点，在人类、小鼠和爪蟾中保守。在本报告中，我们表明 MAML1 在这两个位点都被 SUMO 化。E2 连接酶 UBC9 是 MAML1 SUMO 化所必需的，E3 连接酶 PIAS1 刺激此活性。赖氨酸的突变会使 MAML1 的 SUMO 化失活，并在细胞培养测定中强烈增加 MAML1 激活的转录。蛋白酶 SENP1 逆转 MAML1 的 SUMO 化，并增强 MAML1 的转录因子活性。此外，SUMO 化增强了 MAML1 与 HDAC7 的相互作用，从而降低了 MAML1 的转录活性。总之，我们的数据表明，MAML1 的 SUMO 化是通过影响其与 HDAC7 的相互作用来抑制 MAML1 活性的一种机制。
