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

Collins, P. E., Somma, D. , Kerrigan, D., Herrington, F., Keeshan, K. R. , Nibbs, R. J.B. and Carmody, R. J. (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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nibbs, Professor Rob and Kerrigan, Mr David and Carmody, Dr Ruaidhri and Collins, Ms Patricia and Keeshan, Dr Karen and Somma, Domenico and Herrington, Dr Felicity
• Authors: Collins, P. E., Somma, D., Kerrigan, D., Herrington, F., Keeshan, K. R., Nibbs, R. J.B., and Carmody, R. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Proceedings of the National Academy of Sciences of the United States of America
• Publisher: National Academy of Sciences
• ISSN: 0027-8424
• ISSN (Online): 1091-6490
• Published Online: 26 November 2019
• Copyright Holders: Copyright © 2019 the Authors
• First Published: First published in Proceedings of the National Academy of Sciences of the United States of America 116(51):25828-25838
• Publisher Policy: Reproduced under a Creative Commons license

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190815		Dissecting the function of Bcl-3 in NF-kappaB signaling in B cells	Ruaidhri Carmody	Biotechnology and Biological Sciences Research Council (BBSRC)	BB/M003671/1	III - Immunology
190848		Investigating NF-kB p50 phosphorylation and the regulation of transcription	Ruaidhri Carmody	Medical Research Council (MRC)	MR/M010694/1	III - Immunology