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

Nat Commun. 2014 Jul 15;5:4407. doi: 10.1038/ncomms5407.

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.

MeSH terms

  • 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*

Substances

  • Rab8a protein, mouse
  • Toll-Like Receptor 4
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • rab GTP-Binding Proteins