SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages.

Animals Cytokines / metabolism MAP Kinase Signaling System / physiology Macrophages / metabolism Mice, Transgenic Mitogen-Activated Protein Kinase 3 / metabolism Phosphorylation Signal Transduction / physiology Toll-Like Receptor 4 / metabolism Toll-Like Receptors / metabolism
SCIMP Toll-like receptor c-Fos cytokine extracellular-signal-regulated kinase inflammation innate immunity macrophage scaffold

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
07 09 2021
Historique:
received: 15 03 2021
revised: 12 07 2021
accepted: 13 08 2021
entrez: 8 9 2021
pubmed: 9 9 2021
medline: 15 2 2022
Statut: ppublish

Résumé

Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro- and anti-inflammatory functions described. We reveal here that the immune-specific transmembrane adaptor SCIMP is a direct scaffold for Erk1/2 in TLR pathways, with high-resolution, live-cell imaging revealing that SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling. SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production, with these effects being phenocopied by Erk1/2 signaling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro-inflammatory responses in macrophages.

Identifiants

DOI: 10.1016/j.celrep.2021.109662 PMID: 34496234
pubmed: 34496234
pii: S2211-1247(21)01106-2
doi: 10.1016/j.celrep.2021.109662
pii:
doi:

Substances chimiques

Cytokines 0
Toll-Like Receptor 4 0
Toll-Like Receptors 0
Mitogen-Activated Protein Kinase 3 EC 2.7.11.24

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

109662

Informations de copyright

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests. K.S. is a co-inventor on patent applications for NLRP3 inhibitors, which have been licensed to Inflazome, Ltd., a company headquartered in Dublin, Ireland. Inflazome is developing drugs that target the NLRP3 inflammasome to address unmet clinical needs in inflammatory disease. K.S. served on the Scientific Advisory Board of Inflazome in 2016–2017 and consults for Quench Bio USA and Novartis Switzerland.

Auteurs

Richard M Lucas (RM)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Liping Liu (L)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

James E B Curson (JEB)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Yvette W H Koh (YWH)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Neeraj Tuladhar (N)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Nicholas D Condon (ND)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Kaustav Das Gupta (K)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Sabrina S Burgener (SS)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Kate Schroder (K)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Evan Ingley (E)

Cell Signalling Group, Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia; Discipline of Medical, Molecular and Forensic Sciences, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA 6150, Australia.

Matthew J Sweet (MJ)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia.

Jennifer L Stow (JL)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: j.stow@imb.uq.edu.au.

Lin Luo (L)

Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: l.luo@imb.uq.edu.au.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Système de signalisation des MAP kinases › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Mitogen-Activated Protein Kinases › Extracellular Signal-Regulated MAP Kinases › Mitogen-Activated Protein Kinase 3 › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Métabolisme › Phosphorylation › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs de reconnaissance de motifs moléculaires › Récepteurs de type Toll › Récepteur de type Toll-4 › SCIMP is a spatiotemporal transmembrane...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs immunologiques › Récepteurs de reconnaissance de motifs moléculaires › Récepteurs de type Toll › SCIMP is a spatiotemporal transmembrane...