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

Cell Rep. 2021 Sep 7;36(10):109662. doi: 10.1016/j.celrep.2021.109662.


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.

Keywords: SCIMP; Toll-like receptor; c-Fos; cytokine; extracellular-signal-regulated kinase; inflammation; innate immunity; macrophage; scaffold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Cytokines
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Mitogen-Activated Protein Kinase 3