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

Lucas, R.M., Liu, L., Curson, J.E.B., Koh, Y.W.H., Tuladhar, N., Condon, N.D., Das Gupta, K., Burgener, S.S., Schroder, K., Ingley, E.ORCID: 0000-0002-8112-9134, Sweet, M.J., Stow, J.L. and Luo, L. (2021) SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages. Cell Reports, 36 (10). Art. 109662.

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Abstract

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.

Item Type: Journal Article
Murdoch Affiliation(s): Medical, Molecular and Forensic Sciences
Publisher: Elsevier Inc.
Copyright: © 2021 The Authors.
URI: http://researchrepository.murdoch.edu.au/id/eprint/62152
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