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The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2.
PLoS Pathog 2019; 15(3):e1007684PP

Abstract

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.

Authors+Show Affiliations

Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States of America.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway. Department for Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo Norway.Molecular Cell Biology Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. The Central Norway Regional Health Authority, St. Olavs Hospital HF, Trondheim, Norway.Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. The Central Norway Regional Health Authority, St. Olavs Hospital HF, Trondheim, Norway.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30883606

Citation

Skjesol, Astrid, et al. "The TLR4 Adaptor TRAM Controls the Phagocytosis of Gram-negative Bacteria By Interacting With the Rab11-family Interacting Protein 2." PLoS Pathogens, vol. 15, no. 3, 2019, pp. e1007684.
Skjesol A, Yurchenko M, Bösl K, et al. The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2. PLoS Pathog. 2019;15(3):e1007684.
Skjesol, A., Yurchenko, M., Bösl, K., Gravastrand, C., Nilsen, K. E., Grøvdal, L. M., ... Husebye, H. (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), pp. e1007684. doi:10.1371/journal.ppat.1007684.
Skjesol A, et al. The TLR4 Adaptor TRAM Controls the Phagocytosis of Gram-negative Bacteria By Interacting With the Rab11-family Interacting Protein 2. PLoS Pathog. 2019;15(3):e1007684. PubMed PMID: 30883606.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The TLR4 adaptor TRAM controls the phagocytosis of Gram-negative bacteria by interacting with the Rab11-family interacting protein 2. AU - Skjesol,Astrid, AU - Yurchenko,Mariia, AU - Bösl,Korbinian, AU - Gravastrand,Caroline, AU - Nilsen,Kaja Elisabeth, AU - Grøvdal,Lene Melsæther, AU - Agliano,Federica, AU - Patane,Francesco, AU - Lentini,Germana, AU - Kim,Hera, AU - Teti,Giuseppe, AU - Kumar Sharma,Aditya, AU - Kandasamy,Richard K, AU - Sporsheim,Bjørnar, AU - Starheim,Kristian K, AU - Golenbock,Douglas T, AU - Stenmark,Harald, AU - McCaffrey,Mary, AU - Espevik,Terje, AU - Husebye,Harald, Y1 - 2019/03/18/ PY - 2018/06/04/received PY - 2019/03/07/accepted PY - 2019/03/28/revised PY - 2019/3/19/pubmed PY - 2019/4/12/medline PY - 2019/3/19/entrez SP - e1007684 EP - e1007684 JF - PLoS pathogens JO - PLoS Pathog. VL - 15 IS - 3 N2 - 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. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/30883606/The_TLR4_adaptor_TRAM_controls_the_phagocytosis_of_Gram-negative_bacteria_by_interacting_with_the_Rab11-family_interacting_protein_2 L2 - http://dx.plos.org/10.1371/journal.ppat.1007684 DB - PRIME DP - Unbound Medicine ER -