Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling

Lin Luo, Adam A Wall, Jeremy C Yeo, Nicholas D Condon, Suzanne J Norwood, Simone Marianne Schoenwaelder, Kaiwen W Chen, Shaun Jackson, Brendan John Jenkins, Elizabeth Louise Hartland, Kate Schroder, Brett Martin Collins, Matthew James Sweet, Jennifer L Stow

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Abstract

Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS) to mount innate immune responses. The TLR4-induced release of pro- and anti-inflammatory cytokines generates robust inflammatory responses, which must then be restrained to avoid disease. New mechanisms for the critical regulation of TLR-induced cytokine responses are still emerging. Here we find TLR4 complexes localized in LPS-induced dorsal ruffles on the surface of macrophages. We discover that the small GTPase Rab8a is enriched in these ruffles and recruits phosphatidylinositol 3-kinase (PI3K 3) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3K 3 function to regulate Akt signalling generated by surface TLR4. Rab8a and PI3K 3 do not affect TLR4 endocytosis, but instead regulate mammalian target of rapamycin signalling as a mechanism for biasing the cytokine profile to constrain inflammation in innate immunity. ? 2014 Macmillan Publishers Limited. All rights reserved
Original languageEnglish
Pages (from-to)1 - 13
Number of pages13
JournalNature Communications
Volume5
Issue number(Art. No.:4407)
DOIs
Publication statusPublished - 2014

Cite this

Luo, L., Wall, A. A., Yeo, J. C., Condon, N. D., Norwood, S. J., Schoenwaelder, S. M., ... Stow, J. L. (2014). Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling. Nature Communications, 5((Art. No.:4407)), 1 - 13. https://doi.org/10.1038/ncomms5407
Luo, Lin ; Wall, Adam A ; Yeo, Jeremy C ; Condon, Nicholas D ; Norwood, Suzanne J ; Schoenwaelder, Simone Marianne ; Chen, Kaiwen W ; Jackson, Shaun ; Jenkins, Brendan John ; Hartland, Elizabeth Louise ; Schroder, Kate ; Collins, Brett Martin ; Sweet, Matthew James ; Stow, Jennifer L. / Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling. In: Nature Communications. 2014 ; Vol. 5, No. (Art. No.:4407). pp. 1 - 13.
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abstract = "Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS) to mount innate immune responses. The TLR4-induced release of pro- and anti-inflammatory cytokines generates robust inflammatory responses, which must then be restrained to avoid disease. New mechanisms for the critical regulation of TLR-induced cytokine responses are still emerging. Here we find TLR4 complexes localized in LPS-induced dorsal ruffles on the surface of macrophages. We discover that the small GTPase Rab8a is enriched in these ruffles and recruits phosphatidylinositol 3-kinase (PI3K 3) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3K 3 function to regulate Akt signalling generated by surface TLR4. Rab8a and PI3K 3 do not affect TLR4 endocytosis, but instead regulate mammalian target of rapamycin signalling as a mechanism for biasing the cytokine profile to constrain inflammation in innate immunity. ? 2014 Macmillan Publishers Limited. All rights reserved",
author = "Lin Luo and Wall, {Adam A} and Yeo, {Jeremy C} and Condon, {Nicholas D} and Norwood, {Suzanne J} and Schoenwaelder, {Simone Marianne} and Chen, {Kaiwen W} and Shaun Jackson and Jenkins, {Brendan John} and Hartland, {Elizabeth Louise} and Kate Schroder and Collins, {Brett Martin} and Sweet, {Matthew James} and Stow, {Jennifer L}",
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Luo, L, Wall, AA, Yeo, JC, Condon, ND, Norwood, SJ, Schoenwaelder, SM, Chen, KW, Jackson, S, Jenkins, BJ, Hartland, EL, Schroder, K, Collins, BM, Sweet, MJ & Stow, JL 2014, 'Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling', Nature Communications, vol. 5, no. (Art. No.:4407), pp. 1 - 13. https://doi.org/10.1038/ncomms5407

Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling. / Luo, Lin; Wall, Adam A; Yeo, Jeremy C; Condon, Nicholas D; Norwood, Suzanne J; Schoenwaelder, Simone Marianne; Chen, Kaiwen W; Jackson, Shaun; Jenkins, Brendan John; Hartland, Elizabeth Louise; Schroder, Kate; Collins, Brett Martin; Sweet, Matthew James; Stow, Jennifer L.

In: Nature Communications, Vol. 5, No. (Art. No.:4407), 2014, p. 1 - 13.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Wall, Adam A

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AU - Schoenwaelder, Simone Marianne

AU - Chen, Kaiwen W

AU - Jackson, Shaun

AU - Jenkins, Brendan John

AU - Hartland, Elizabeth Louise

AU - Schroder, Kate

AU - Collins, Brett Martin

AU - Sweet, Matthew James

AU - Stow, Jennifer L

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AB - Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS) to mount innate immune responses. The TLR4-induced release of pro- and anti-inflammatory cytokines generates robust inflammatory responses, which must then be restrained to avoid disease. New mechanisms for the critical regulation of TLR-induced cytokine responses are still emerging. Here we find TLR4 complexes localized in LPS-induced dorsal ruffles on the surface of macrophages. We discover that the small GTPase Rab8a is enriched in these ruffles and recruits phosphatidylinositol 3-kinase (PI3K 3) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3K 3 function to regulate Akt signalling generated by surface TLR4. Rab8a and PI3K 3 do not affect TLR4 endocytosis, but instead regulate mammalian target of rapamycin signalling as a mechanism for biasing the cytokine profile to constrain inflammation in innate immunity. ? 2014 Macmillan Publishers Limited. All rights reserved

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Luo L, Wall AA, Yeo JC, Condon ND, Norwood SJ, Schoenwaelder SM et al. Rab8a interacts directly with PI3Kgamma to modulate TLR4-driven PI3K and mTOR signalling. Nature Communications. 2014;5((Art. No.:4407)):1 - 13. https://doi.org/10.1038/ncomms5407