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

Luo, L; Bokil, NJ; Wall, AA; Kapetanovic, R; Lansdaal, NM; Marceline, F; Burgess, BJ; Tong, SJ; Guo, Z; Alexandrov, K; Ross, IL; Hibbs, ML; Stow, JL; Sweet, MJ

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

Luo, L Bokil, NJ

Wall, AA Kapetanovic, R Lansdaal, NM Marceline, F Burgess, BJ Tong, SJ Guo, Z Alexandrov, K Ross, IL Hibbs, ML Stow, JL Sweet, MJ

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Publication Type:: Journal Article
Citation:: Nature Communications, 2017, 8
Issue Date:: 2017-01-18

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Field	Value	Language
dc.contributor.author	Luo, L	en_US
dc.contributor.author	Bokil, NJ https://orcid.org/0000-0003-3202-9249	en_US
dc.contributor.author	Wall, AA	en_US
dc.contributor.author	Kapetanovic, R	en_US
dc.contributor.author	Lansdaal, NM	en_US
dc.contributor.author	Marceline, F	en_US
dc.contributor.author	Burgess, BJ	en_US
dc.contributor.author	Tong, SJ	en_US
dc.contributor.author	Guo, Z	en_US
dc.contributor.author	Alexandrov, K	en_US
dc.contributor.author	Ross, IL	en_US
dc.contributor.author	Hibbs, ML	en_US
dc.contributor.author	Stow, JL	en_US
dc.contributor.author	Sweet, MJ	en_US
dc.date.available	2016-12-02	en_US
dc.date.issued	2017-01-18	en_US
dc.identifier.citation	Nature Communications, 2017, 8	en_US
dc.identifier.uri	http://hdl.handle.net/10453/123937
dc.description.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-? B, 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.	en_US
dc.relation.ispartof	Nature Communications	en_US
dc.relation.isbasedon	10.1038/ncomms14133	en_US
dc.subject.mesh	Macrophages	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	src-Family Kinases	en_US
dc.subject.mesh	Interleukin-6	en_US
dc.subject.mesh	Cytokines	en_US
dc.subject.mesh	Protein Binding	en_US
dc.subject.mesh	Toll-Like Receptor 4	en_US
dc.subject.mesh	Interleukin-12 Subunit p40	en_US
dc.subject.mesh	Protein Domains	en_US
dc.title	SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages	en_US
dc.type	Journal Article
utslib.citation.volume	8	en_US
utslib.for	1103 Clinical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.publication-status	Published	en_US
pubs.volume	8	en_US

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-? B, 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.

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http://hdl.handle.net/10453/123937