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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64 Citations (Scopus)

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

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