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

Luo, Lin, Wall, Adam A., Yeo, Jeremy C., Condon, Nicholas D., Norwood, Suzanne J., Schoenwaelder, Simone, Chen, Kaiwen W., Jackson, Shaun, Jenkins, Brendan J., Hartland, Elizabeth L., Schroder, Kate, Collins, Brett M., Sweet, Matthew J. and Stow, Jennifer L. (2014) Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling. Nature Communications, 5 4407.1-4407.13. doi:10.1038/ncomms5407

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Author Luo, Lin
Wall, Adam A.
Yeo, Jeremy C.
Condon, Nicholas D.
Norwood, Suzanne J.
Schoenwaelder, Simone
Chen, Kaiwen W.
Jackson, Shaun
Jenkins, Brendan J.
Hartland, Elizabeth L.
Schroder, Kate
Collins, Brett M.
Sweet, Matthew J.
Stow, Jennifer L.
Title Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2014-07-15
Year available 2014
Sub-type Article (original research)
DOI 10.1038/ncomms5407
Open Access Status File (Publisher version)
Volume 5
Start page 4407.1
End page 4407.13
Total pages 13
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 606788
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 31 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 30 times in Scopus Article | Citations
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