Institute of Pathology, University of Ulm, Albert-Einstein-Allee 23, 89070, Ulm, Germany.
Department of Pathology, Qena Faculty of Medicine, South Valley University, Qena, 83523, Egypt.
Sci Rep. 2018 Jan 22;8(1):1352. doi: 10.1038/s41598-018-19822-z.
Glycogen synthase kinase 3β (GSK3β) is a ubiquitously expressed serine/threonine kinase involved in the regulation of various cellular functions, such as energy homoeostasis, cell growth and developmental processes. More recently, GSK3β has been identified as a part of a protein complex involved in the regulation of the CARMA1-BCL10-MALT1 complex (CBM complex) formation, which is a key signalling event upon antigen receptor engagement of B and T cells, required for the activation of the NF-κB and JNK pathways. However, conflicting reports have been published regarding the role of GSK3β for the activation of the NF-κB signalling pathways. Therefore, we aimed to determine the impact of GSK3β on the NF-κB signalling induced upon T cell activation. Blocking GSK3β by either pharmacologic inhibitors (SB216763 and SB415286) or by RNAi caused a reduced proteolysis of the MALT1 targets CYLD1, BCL10 and RelB as well as diminished IκBα degradation, NF-κB DNA binding and NF-κB activity. This negative effect on NF-κB appears to be due to a diminished CBM complex formation caused by a reduced BCL10 phosphorylation. Taken together, we provide here evidence for a novel regulatory mechanism by which GSK3β affects NF-κB signalling in activated T cells.
糖原合酶激酶 3β（GSK3β）是一种普遍表达的丝氨酸/苏氨酸激酶，参与调节各种细胞功能，如能量平衡、细胞生长和发育过程。最近，GSK3β被确定为参与调节 CARMA1-BCL10-MALT1 复合物（CBM 复合物）形成的蛋白质复合物的一部分，该复合物是 B 和 T 细胞抗原受体结合后激活 NF-κB 和 JNK 途径的关键信号事件，对于 NF-κB 和 JNK 途径的激活是必需的。然而，关于 GSK3β 对于 NF-κB 信号通路的激活作用，已经发表了相互矛盾的报道。因此，我们旨在确定 GSK3β 对 T 细胞激活诱导的 NF-κB 信号的影响。通过药理学抑制剂（SB216763 和 SB415286）或 RNAi 阻断 GSK3β 会导致 MALT1 靶标 CYLD1、BCL10 和 RelB 的蛋白水解减少，以及 IκBα 降解、NF-κB DNA 结合和 NF-κB 活性降低。这种对 NF-κB 的负效应似乎是由于 BCL10 磷酸化减少导致 CBM 复合物形成减少所致。总之，我们在这里提供了证据，证明 GSK3β 通过一种新的调节机制影响激活的 T 细胞中的 NF-κB 信号。
