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, Matthew J. Sweet

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12 Citations (Scopus)

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.

Original languageEnglish
Article number14133
Number of pages14
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 18 Jan 2017

Cite this

Luo, L., Bokil, N. J., Wall, A. A., Kapetanovic, R., Lansdaal, N. M., Marceline, F., ... Sweet, M. J. (2017). SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. Nature Communications, 8, [14133]. https://doi.org/10.1038/ncomms14133
Luo, Lin ; Bokil, Nilesh J. ; Wall, Adam A. ; Kapetanovic, Ronan ; Lansdaal, Natalie M. ; Marceline, Faustine ; Burgess, Belinda J. ; Tong, Samuel J. ; Guo, Zhong ; Alexandrov, Kirill ; Ross, Ian L. ; Hibbs, Margaret L. ; Stow, Jennifer L. ; Sweet, Matthew J. / SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. In: Nature Communications. 2017 ; Vol. 8.
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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-? 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.",
author = "Lin Luo and Bokil, {Nilesh J.} and Wall, {Adam A.} and Ronan Kapetanovic and Lansdaal, {Natalie M.} and Faustine Marceline and Burgess, {Belinda J.} and Tong, {Samuel J.} and Zhong Guo and Kirill Alexandrov and Ross, {Ian L.} and Hibbs, {Margaret L.} and Stow, {Jennifer L.} and Sweet, {Matthew J.}",
year = "2017",
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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 2017, 'SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages', Nature Communications, vol. 8, 14133. https://doi.org/10.1038/ncomms14133

SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages. / Luo, Lin; Bokil, Nilesh J.; Wall, Adam A.; Kapetanovic, Ronan; Lansdaal, Natalie M.; Marceline, Faustine; Burgess, Belinda J.; Tong, Samuel J.; Guo, Zhong; Alexandrov, Kirill; Ross, Ian L.; Hibbs, Margaret L.; Stow, Jennifer L.; Sweet, Matthew J.

In: Nature Communications, Vol. 8, 14133, 18.01.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory cytokine production from macrophages

AU - Luo, Lin

AU - Bokil, Nilesh J.

AU - Wall, Adam A.

AU - Kapetanovic, Ronan

AU - Lansdaal, Natalie M.

AU - Marceline, Faustine

AU - Burgess, Belinda J.

AU - Tong, Samuel J.

AU - Guo, Zhong

AU - Alexandrov, Kirill

AU - Ross, Ian L.

AU - Hibbs, Margaret L.

AU - Stow, Jennifer L.

AU - Sweet, Matthew J.

PY - 2017/1/18

Y1 - 2017/1/18

N2 - 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.

AB - 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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