The IκB-protein BCL-3 controls toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus (original) (raw)

Collins, Patricia E., Somma, Domenico ORCID: https://orcid.org/0000-0003-2486-7250, Kerrigan, David, Herrington, Felicity, Keeshan, Karen R. ORCID: https://orcid.org/0000-0001-7266-0890, Nibbs, Robert J.B. ORCID: https://orcid.org/0000-0002-8150-0044 and Carmody, Ruaidhri J. ORCID: https://orcid.org/0000-0002-9474-4507(2019) The IκB-protein BCL-3 controls toll-like receptor-induced MAPK activity by promoting TPL-2 degradation in the nucleus.Proceedings of the National Academy of Sciences of the United States of America, 116(51), pp. 25828-25838. (doi: 10.1073/pnas.1900408116) (PMID:31772019) (PMCID:PMC6926074)

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.

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Funder and Project Information

Dissecting the function of Bcl-3 in NF-kappaB signaling in B cells

Ruaidhri Carmody

BB/M003671/1

III - Immunology

Investigating NF-kB p50 phosphorylation and the regulation of transcription

Ruaidhri Carmody

MR/M010694/1

III - Immunology

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