Poster Presentation The 47th Lorne Conference on Protein Structure and Function 2022

SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages   (#203)

Lin Luo 1 , Richard M Lucas 1 , Kate Schroder 1 , Evan Ingley 2 , Matthew J Sweet 1 , Jennifer L Stow 1
  1. Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, QLD, Australia
  2. Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, WA 6009, Perth, WA, Australia

Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues1. The role of extracellular signal-regulated kinases 1/2 (Erk1/2) in TLR signalling 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 signalling. 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 signalling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold2 3 for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro- inflammatory responses in macrophages.

 

  1. [1] Luo, L., Lucas, R. M., Liu, L., and Stow, J. L. (2020) Signalling, sorting and scaffolding adaptors for Toll-like receptors, Joural of Cell Science 133. [2] Luo, L., ... Stow, J. L., and Sweet, M. J. (2017) SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages, Nature Communications 8, 14133. [3] Luo, L., .... M., Sweet, M. J., and Stow, J. L. (2019) SCIMP is a universal Toll-like receptor adaptor in macrophages, Journal of Leukocyte Biolology, 1-12.