title: Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling.
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.
authors.affiliation: 1] Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: 1] Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia [2].
authors.forename: Adam A
authors.initials: AA
authors.lastname: Wall
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Yeo
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Condon
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Norwood
authors.affiliation: 1] Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia [2] Heart Research Institute & Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Simone
authors.initials: S
authors.lastname: Schoenwaelder
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Kaiwen W
authors.initials: KW
authors.lastname: Chen
authors.affiliation: 1] Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia [2] Heart Research Institute & Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Shaun
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria 3168, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.affiliation: Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3010, Australia.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Hartland
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D051197:Toll-Like Receptor 4; D020691:rab GTP-Binding Proteins; C546061:Rab8a protein, mouse