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

Author

Listed:
  • 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
    Heart Research Institute & Charles Perkins Centre, The University of Sydney)

  • Kaiwen W. Chen

    (Institute for Molecular Bioscience, The University of Queensland)

  • Shaun Jackson

    (Australian Centre for Blood Diseases, Monash University
    Heart Research Institute & Charles Perkins Centre, The University of Sydney)

  • 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)

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.

Suggested Citation

  • 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 & , 2014. "Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5407
    DOI: 10.1038/ncomms5407
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    Cited by:

    1. Gloria Ursino & Giorgio Ramadori & Anna Höfler & Soline Odouard & Pryscila D. S. Teixeira & Florian Visentin & Christelle Veyrat-Durebex & Giulia Lucibello & Raquel Firnkes & Serena Ricci & Claudia R., 2022. "Hepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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