Nat Immunol. 2012 Nov;13(11):1045-54. doi: 10.1038/ni.2426.
The p110d isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock.
Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno-Martin I, Nock G, Filloux A, Beyaert R, Flamand V, Vanhaesebroeck B.
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK. e.aksoy@qmul.ac.uk
Lipopolysaccharide activates plasma-membrane signaling and endosomal signaling by Toll-like receptor 4 (TLR4) through the TIRAP-MyD88 and TRAM-TRIF adaptor complexes, respectively, but it is unclear how the signaling switch between these cell compartments is coordinated. In dendritic cells, we found that the p110d isoform of phosphatidylinositol-3-OH kinase (PI(3)K) induced internalization of TLR4 and dissociation of TIRAP from the plasma membrane, followed by calpain-mediated degradation of TIRAP. Accordingly, inactivation of p110d prolonged TIRAP-mediated signaling from the plasma membrane, which augmented proinflammatory cytokine production while decreasing TRAM-dependent endosomal signaling that generated anti-inflammatory cytokines (interleukin 10 and interferon-ß). In line with that altered signaling output, p110d-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110d balances overall homeostasis in the TLR4 pathway. |
