SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages

Lin Luo, Nilesh J. Bokil, Adam A. Wall, Ronan Kapetanovic, Natalie M. Lansdaal, Faustine Marceline, Belinda J. Burgess, Samuel J. Tong, Zhong Guo, Kirill Alexandrov, Ian L. Ross, Margaret L. Hibbs, Jennifer L. Stow () and Matthew J. Sweet ()
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Lin Luo: Institute for Molecular Bioscience (IMB), The University of Queensland
Nilesh J. Bokil: Institute for Molecular Bioscience (IMB), The University of Queensland
Adam A. Wall: Institute for Molecular Bioscience (IMB), The University of Queensland
Ronan Kapetanovic: Institute for Molecular Bioscience (IMB), The University of Queensland
Natalie M. Lansdaal: Institute for Molecular Bioscience (IMB), The University of Queensland
Faustine Marceline: Institute for Molecular Bioscience (IMB), The University of Queensland
Belinda J. Burgess: Institute for Molecular Bioscience (IMB), The University of Queensland
Samuel J. Tong: Institute for Molecular Bioscience (IMB), The University of Queensland
Zhong Guo: Institute for Molecular Bioscience (IMB), The University of Queensland
Kirill Alexandrov: Institute for Molecular Bioscience (IMB), The University of Queensland
Ian L. Ross: Institute for Molecular Bioscience (IMB), The University of Queensland
Margaret L. Hibbs: Alfred Medical Research and Education Precinct, Monash University
Jennifer L. Stow: Institute for Molecular Bioscience (IMB), The University of Queensland
Matthew J. Sweet: Institute for Molecular Bioscience (IMB), The University of Queensland

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Danger signals activate Toll-like receptors (TLRs), thereby initiating inflammatory responses. Canonical TLR signalling, via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-κB, occurs in many cell types; however, additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP, an immune-restricted, transmembrane adaptor protein (TRAP), promotes selective proinflammatory cytokine responses by direct modulation of TLR4. SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. Point mutations in SCIMP abrogating TLR4 binding also prevent SCIMP-mediated cytokine production. SCIMP is, therefore, an immune-specific TLR adaptor that shapes host defence and inflammation.

Date: 2017
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DOI: 10.1038/ncomms14133

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