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The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

ABSTRACT: Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of active TPL-2 is a critical mechanism limiting TLR-induced MAPK activity. We reveal that TPL-2 is a nucleocytoplasmic shuttling protein and identify the nucleus as the primary site for TPL-2 degradation. BCL-3 interacts with TPL-2 and promotes its degradation by promoting its nuclear localization. As a consequence, Bcl3 ^-/- macrophages have increased TPL-2 stability following TLR stimulation, leading to increased MAPK activity and MAPK-dependent responses. Moreover, BCL-3-mediated regulation of TPL-2 stability sets the MAPK activation threshold and determines the amount of TLR ligand required to initiate the production of inflammatory cytokines. Thus, the nucleus is a key site in the regulation of TLR-induced MAPK activity. BCL-3 links control of the MAPK and NF-ĸB pathways in the nucleus, and BCL-3-mediated TPL-2 regulation impacts on the cellular decision to initiate proinflammatory cytokine production in response to TLR activation.

SUBMITTER: Collins PE

PROVIDER: S-EPMC6926074 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

Collins Patricia E PE Somma Domenico D Kerrigan David D Herrington Felicity F Keeshan Karen K Nibbs Robert J B RJB Carmody Ruaidhrí J RJ

Proceedings of the National Academy of Sciences of the United States of America 20191126 51

Proinflammatory responses induced by Toll-like receptors (TLRs) are dependent on the activation of the NF-ĸB and mitogen-activated protein kinase (MAPK) pathways, which coordinate the transcription and synthesis of proinflammatory cytokines. We demonstrate that BCL-3, a nuclear IĸB protein that regulates NF-ĸB, also controls TLR-induced MAPK activity by regulating the stability of the TPL-2 kinase. TPL-2 is essential for MAPK activation by TLR ligands, and the rapid proteasomal degradation of ac ...[more]

PMID: 31772019

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Project description:Intervertebral disc degeneration (IDD) is a common disease with a high morbidity rate, which results in a significant deterioration in the quality of life of patients. MicroRNAs (miRNAs/miRs) are a class of endogenous small non-coding RNAs that influence target genes and serve critical roles in numerous biological processes. However, the role of miR-489-3p in lumbar disc degeneration is yet to be elucidated. In the present study, human NP cells were treated with 10 ng/ml lipopolysaccharide (LPS) for 24 h to investigate the role of miR-489-3p in IDD in an in vitro model. Reverse transcription-quantitative (RT-q)PCR was performed to determine the expression levels of miR-489-3p. Then, the TargetScan database was used to predict the potential binding sites between miR-489-3p and Toll-like receptor (TLR)4, and a dual-luciferase reporter assay was performed to verify the findings. Subsequently, RT-qPCR and western blotting were used to analyze the expression levels of TLR4. In addition, human nucleus pulposus (NP) cells were transfected with a miR-489-3p mimic and TLR4 overexpression plasmid to study the effects of miR-489-3p on LPS-induced human NP cells. Cell apoptosis and cell viability were also determined using flow cytometry and MTT assays, respectively. Finally, ELISAs were performed to analyze the levels of inflammatory factors. The expression levels of miR-489-3p were discovered to be downregulated in LPS-treated human NP cells. In addition, TLR4 was revealed to be a direct target gene of miR-489-3p, and its expression levels were upregulated in LPS-treated human NP cells. miR-489-3p was found to inhibit the LPS-induced decreases in cell viability and increases in apoptosis, and the concentration of inflammatory cytokines. Furthermore, miR-489-3p suppressed the LPS-induced decreases in extracellular matrix deposition via decreasing the expression levels of aggrecan and collagen type II in human NP cells. Finally, the results revealed that miR-489-3p inhibited the LPS-induced activation of the NF-κB signaling pathway in human NP cells. Conversely, all of the effects of miR-489-3p on LPS-induced human NP cells were reversed by the TLR4 overexpression plasmid. These findings suggested that miR-489-3p may represent a novel therapeutic target for the treatment of IDD.

Dataset Information

The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

Publications

The IκB-protein BCL-3 controls Toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.

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