| First Author | Aksoy E | Year | 2012 |
| Journal | Nat Immunol | Volume | 13 |
| Issue | 11 | Pages | 1045-1054 |
| PubMed ID | 23023391 | Mgi Jnum | J:188561 |
| Mgi Id | MGI:5441112 | Doi | 10.1038/ni.2426 |
| Citation | Aksoy E, et al. (2012) The p110delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol 13(11):1045-54 |
| abstractText | 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 p110delta 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 p110delta 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-beta). In line with that altered signaling output, p110delta-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110delta balances overall homeostasis in the TLR4 pathway. |
