The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2
Nilsen, Kaja Elisabeth
Grøvdal, Lene Melsæther
Author summary The Gram-negative bacteria E. coli is the most common cause of severe human pathological conditions like sepsis. Sepsis is a clinical syndrome defined by pathological changes due to systemic inflammation, resulting in paralysis of adaptive T-cell immunity with IFN-β as a critical factor. TLR4 is a key sensing receptor of lipopolysaccharide on Gram-negative bacteria. Inflammatory signalling by TLR4 is initiated by the use of alternative pair of TIR-adapters, MAL-MyD88 or TRAM-TRIF. MAL-MyD88 signaling occurs mainly from the plasma membrane giving pro-inflammatory cytokines like TNF, while TRAM-TRIF signaling occurs from vacuoles like endosomes and phagosomes to give type I interferons like IFN-β. It has previously been shown that TLR4 can control phagocytosis and phagosomal maturation through MAL-MyD88 in mice, however, these data have been disputed and published before the role of TRAM was defined in the induction of IFN-β. A role for TRAM or TRIF in phagocytosis has not previously been reported. Here we describe a novel mechanism where TRAM and its binding partner Rab11-FIP2 control phagocytosis of E. coli and regulate IRF3 dependent production of IFN-β. The significance of these results is that we define Rab11-FIP2 as a potential target for modulation of TLR4-dependent signalling in different pathological states.
Phagocytosis , Toll-like receptor 4 (TLR4) , Rab11 family interacting protein 2 (FIP2)
Skjesol, A., Yurchenko, M., Bösl, K., Gravastrand, C., Nilsen, K.E., Grøvdal, L.M., Agliano, F., Patane, F., Lentini, G., Kim, H. and Teti, G., 2019. The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2. PLoS pathogens, 15(3), (e1007684). DOI:10.1371/journal.ppat.1007684