SCIMP is a universal Toll‐like receptor adaptor in macrophages
2019
In innate immune cells, pathogens and danger signals activate TLRs, unleashing potent and tailored inflammatory responses. Previously, we reported that an immune-specific transmembrane
adaptor, SLP adaptor and CSK interacting membrane protein (SCIMP), interacts with TLR4 via
direct binding to its cytoplasmic TIR domain. SCIMP scaffolds a Src family kinase, Lyn, for TLR4
phosphorylation and activation. Consequently, SCIMP is able to direct selective production of
the proinflammatory cytokines IL-6 and IL-12p40 downstream of TLR4 in macrophages. Here,
we set out to investigate whether SCIMP also acts as an adaptor for other TLR family members.
We report here that SCIMP is phosphorylated and activated in response to agonists of multiple
TLRs, including TLR2, TLR3, TLR4, and TLR9. SCIMP also interacts with TLRs that are known to
signal from both the cell surface and endosomal compartments. In so doing, this transmembrane
adaptor presents Lyn, along with other effectors such as Grb2, Csk, and SLP65, to multiple TLRs
during cellular activation. CRISPR-mediated knockout or silencing of SCIMP in macrophages
alters TLR signaling outputs and the production of IL-6 and IL-12p40 downstream of multiple
TLRs, and upon challenge with live bacteria. Furthermore, the selectivity in cytokine responses
is preserved downstream of TLR3, with inducible expression of Il-12p40 and IL-6, but not IFN,
being SCIMP dependent. SCIMP is thus a universal TLR adaptor for scaffolding the Lyn tyrosine
kinase and its effectors to enable responses against a wide range of danger signals.
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