The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2

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Date
2019-03-18
Authors
Skjesol, Astrid
Yurchenko, Mariia
Bösl, Korbinian
Gravastrand, Caroline
Nilsen, Kaja Elisabeth
Grøvdal, Lene Melsæther
Agliano, Federica
Patane, Francesco
Lentini, Germana
Kim, Hera
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PLoS
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Abstract
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.
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Keywords
Phagocytosis , Toll-like receptor 4 (TLR4) , Rab11 family interacting protein 2 (FIP2)
Citation
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