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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; Somma, Domenico; Kerrigan, David; Herrington, Felicity; Keeshan, Karen; Nibbs, Robert J B; Carmody, Ruaidhrí J.
Afiliación
  • Collins PE; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom.
  • Somma D; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom.
  • Kerrigan D; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom.
  • Herrington F; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom.
  • Keeshan K; Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom.
  • Nibbs RJB; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom.
  • Carmody RJ; Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 0YN, United Kingdom; ruaidhri.carmody@glasgow.ac.uk.
Proc Natl Acad Sci U S A ; 116(51): 25828-25838, 2019 12 17.
Article en En | MEDLINE | ID: mdl-31772019
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Núcleo Celular / Proteínas Proto-Oncogénicas / Quinasas Quinasa Quinasa PAM / Sistema de Señalización de MAP Quinasas / Proteínas I-kappa B / Receptores Toll-Like / Proteínas del Linfoma 3 de Células B Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Núcleo Celular / Proteínas Proto-Oncogénicas / Quinasas Quinasa Quinasa PAM / Sistema de Señalización de MAP Quinasas / Proteínas I-kappa B / Receptores Toll-Like / Proteínas del Linfoma 3 de Células B Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2019 Tipo del documento: Article País de afiliación: Reino Unido