Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling.

Details

Serval ID
serval:BIB_5CA22E66172A
Type
Article: article from journal or magazin.
Collection
Publications
Title
Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling.
Journal
Nature communications
Author(s)
Luo L., Wall A.A., Yeo J.C., Condon N.D., Norwood S.J., Schoenwaelder S., Chen K.W., Jackson S., Jenkins B.J., Hartland E.L., Schroder K., Collins B.M., Sweet M.J., Stow J.L.
ISSN
2041-1723 (Electronic)
ISSN-L
2041-1723
Publication state
Published
Issued date
15/07/2014
Peer-reviewed
Oui
Volume
5
Pages
4407
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
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 (PI3Kγ) as an effector by interacting directly through its Ras-binding domain. Rab8a and PI3Kγ function to regulate Akt signalling generated by surface TLR4. Rab8a and PI3Kγ 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.
Keywords
Animals, Blotting, Western, Enzyme-Linked Immunosorbent Assay, Mass Spectrometry, Mice, Mice, Knockout, Microscopy, Electron, Scanning, Phosphatidylinositol 3-Kinases/genetics, Phosphatidylinositol 3-Kinases/metabolism, Protein Binding, RAW 264.7 Cells, Signal Transduction/genetics, Signal Transduction/physiology, TOR Serine-Threonine Kinases/genetics, TOR Serine-Threonine Kinases/metabolism, Toll-Like Receptor 4/genetics, Toll-Like Receptor 4/metabolism, rab GTP-Binding Proteins/genetics, rab GTP-Binding Proteins/metabolism
Pubmed
Web of science
Create date
22/09/2018 21:07
Last modification date
21/08/2019 6:35
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