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

Lin Luo, Adam A. Wall, Jeremy C. Yeo, Nicholas D. Condon, Suzanne J. Norwood, Simone Schoenwaelder, Kaiwen W. Chen, Shaun Jackson, Brendan J. Jenkins, Elizabeth L. Hartland, Kate Schroder, Brett M. Collins, Matthew J. Sweet and Jennifer L. Stow ()
Additional contact information
Lin Luo: Institute for Molecular Bioscience, The University of Queensland
Adam A. Wall: Institute for Molecular Bioscience, The University of Queensland
Jeremy C. Yeo: Institute for Molecular Bioscience, The University of Queensland
Nicholas D. Condon: Institute for Molecular Bioscience, The University of Queensland
Suzanne J. Norwood: Institute for Molecular Bioscience, The University of Queensland
Simone Schoenwaelder: Australian Centre for Blood Diseases, Monash University
Kaiwen W. Chen: Institute for Molecular Bioscience, The University of Queensland
Shaun Jackson: Australian Centre for Blood Diseases, Monash University
Brendan J. Jenkins: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University
Elizabeth L. Hartland: University of Melbourne at the Peter Doherty Institute for Infection and Immunity
Kate Schroder: Institute for Molecular Bioscience, The University of Queensland
Brett M. Collins: Institute for Molecular Bioscience, The University of Queensland
Matthew J. Sweet: Institute for Molecular Bioscience, The University of Queensland
Jennifer L. Stow: Institute for Molecular Bioscience, The University of Queensland

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5407

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