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

• Published in: PLoS pathogens Vol. 15; no. 3; p. e1007684
• Main Authors: Skjesol, Astrid, Yurchenko, Mariia, Bösl, Korbinian, Gravastrand, Caroline, Nilsen, Kaja Elisabeth, Grøvdal, Lene Melsæther, Agliano, Federica, Patane, Francesco, Lentini, Germana, Kim, Hera, Teti, Giuseppe, Kumar Sharma, Aditya, Kandasamy, Richard K., Sporsheim, Bjørnar, Starheim, Kristian K., Golenbock, Douglas T., Stenmark, Harald, McCaffrey, Mary, Espevik, Terje, Husebye, Harald
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.03.2019; Public Library of Science (PLoS)
• Subjects: Actin; Activation; Adapters; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Animals; Bacteria; Biology and Life Sciences; Cancer; Carrier Proteins - metabolism; Carrier Proteins - physiology; cdc42 GTP-Binding Protein; Cdc42 protein; Cellular signal transduction; Cytological research; E coli; Endocytosis; Endosomes; Escherichia coli; Escherichia coli - pathogenicity; Funding; G proteins; Gram-negative bacteria; HEK293 Cells; Hospitals; Humans; Immune system; Immunology; Inflammation; Interferon Regulatory Factor-3; Light rail transit; Lipopolysaccharides; Macrophages; Macrophages - immunology; Macrophages - metabolism; Medical research; Medicine; Medicine and Health Sciences; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Microorganisms; Monocytes; Myeloid Differentiation Factor 88; Phagocytes; Phagocytosis; Phagocytosis - physiology; Physiological aspects; Primary Cell Culture; Protein Transport; Protein-protein interactions; Proteins; rab GTP-Binding Proteins; rac1 GTP-Binding Protein; Rac1 protein; Research and Analysis Methods; Signal Transduction; Software; Staphylococcus aureus; Staphylococcus aureus - pathogenicity; Staphylococcus aureus infections; THP-1 Cells; TLR4; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Norway; Italy
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007684

Phagocytosis is a complex process that eliminates microbes and is performed by specialised cells such as macrophages. Toll-like receptor 4 (TLR4) is expressed on the surface of macrophages and recognizes Gram-negative bacteria. Moreover, TLR4 has been suggested to play a role in the phagocytosis of Gram-negative bacteria, but the mechanisms remain unclear. Here we have used primary human macrophages and engineered THP-1 monocytes to show that the TLR4 sorting adapter, TRAM, is instrumental for phagocytosis of Escherichia coli as well as Staphylococcus aureus. We find that TRAM forms a complex with Rab11 family interacting protein 2 (FIP2) that is recruited to the phagocytic cups of E. coli. This promotes activation of the actin-regulatory GTPases Rac1 and Cdc42. Our results show that FIP2 guided TRAM recruitment orchestrates actin remodelling and IRF3 activation, two events that are both required for phagocytosis of Gram-negative bacteria.