Abstract
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.
Highlights
Engagement of the antigen receptors, T cell receptor (TCR) in case of T cells and B cell receptor (BCR) in case of
PMA + ionomycin (P/I) stimulation of Jurkat-shControl cells caused a distinct proteolysis of CYLD1, which is indicated by the reduction of the full length CYLD1 with a molecular weight of approximately 120 kDa and the appearance of an additional CYLD1 specific signal at ≈70 kDa (ΔCYLD1), representing the C-terminal cleavage product of CYLD1 (Fig. 1B, upper panel)
The β-catenin levels were stabilized upon SB21 pre-treatment of P/I-stimulated Jurkat cells underscoring the efficacy of the Glycogen synthase kinase 3β (GSK3β) inhibition achieved by SB21 pre-treatment
Summary
Engagement of the antigen receptors, T cell receptor (TCR) in case of T cells and B cell receptor (BCR) in case of. This IKK2 mediated BCL10 phosphorylation exerts a dual function: Firstly, it is required for the formation of the CBM complex and has a positive effect on NF-κB activation. IKK2-mediated BCL10 phosphorylation weakens the BCL10-MALT1 interaction, which is crucial for the function of the CBM-complex. IKK2 mediated BCL10 phosphorylation exerts both a positive as well as a negative effect on the CBM complex formation and subsequent NF-κB activation. MALT1 is required for activation of the canonical NF-κB pathway induced upon TCR or BCR engagement. A20 and RelB are not the only targets of the MALT1 endoprotease activity Another targets are BCL10, haem-oxidized IRP2 ubiquitin ligase 1 (HOIL-1), Regnase and Roquin 1, and Cylindromatosis (CYLD1), whose cleavage is required for c-Jun www.nature.com/scientificreports/
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