title: SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages.
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.
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Bokil
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Wall
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Ronan
authors.initials: R
authors.lastname: Kapetanovic
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Lansdaal
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Faustine
authors.initials: F
authors.lastname: Marceline
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Burgess
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Tong
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Kirill
authors.initials: K
authors.lastname: Alexandrov
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Ian L
authors.identifier: 0000-0002-2389-4292
authors.initials: IL
authors.lastname: Ross
authors.affiliation: Department of Immunology and Pathology, Alfred Medical Research and Education Precinct, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Hibbs
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.affiliation: Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, Queensland 4072, Australia.|IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D000072417:Protein Domains; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D051197:Toll-Like Receptor 4; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases