FIP2 promotes E. coli-induced IFN-β production and phagocytosis, through its interaction with TRAM

The Toll-like receptor 4 (TLR4) senses LPS from Gram-negative bacteria and triggers two distinct signaling pathways by the use of distinct pairs of signaling adaptors. Following activation at the plasma membrane the adaptors pair TIRAP and MyD88 are immediately recruited, leading to induction of pro-inflammatory cytokines. However, TLR4 located on the phagosomal membrane induces the type I interferons such as IFN-β, through the adaptor pair TRAM and TRIF. The small GTPase Rab11a is involved in the TLR4-induced IFN- β production, delivering TLR4 and TRAM to E. coli phagosomes. Here we report that the Rab11a effector protein, Rab11-FIP2, binds TRAM promoting its delivery to forming E. coli phagosomes and that both Rab11-FIP2 and TRAM are involved in phagocytosis of E. coli in human macrophages. These results show that FIP2 and TRAM are effectors involved in the E. coli-induced IFN- β induction and phagocytosis, which may point at new strategies for treatment Gram-negative induced inflammation that in severe cases may result in the development of sepsis.