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

  • PLoS Pathog. 2019 Mar 18;15(3):e1007684. doi: 10.1371/journal.ppat.1007684.
Astrid Skjesol  1 ,  Mariia Yurchenko  1 ,  Korbinian Bösl  1 ,  Caroline Gravastrand  1 ,  Kaja Elisabeth Nilsen  1 ,  Lene Melsæther Grøvdal  1 ,  Federica Agliano  1  2 ,  Francesco Patane  1  2 ,  Germana Lentini  1  2 ,  Hera Kim  1 ,  Giuseppe Teti  2 ,  Aditya Kumar Sharma  1 ,  Richard K Kandasamy  1 ,  Bjørnar Sporsheim  1 ,  Kristian K Starheim  1 ,  Douglas T Golenbock  3 ,  Harald Stenmark  1  4  5 ,  Mary McCaffrey  6 ,  Terje Espevik  1  7 ,  Harald Husebye  1  7
Affiliations
  • 1. Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
  • 2. Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
  • 3. Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States of America.
  • 4. Centre for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 5. Department for Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo Norway.
  • 6. Molecular Cell Biology Laboratory, Biochemistry Department, Biosciences Institute, University College Cork, Cork, Ireland.
  • 7. The Central Norway Regional Health Authority, St. Olavs Hospital HF, Trondheim, Norway.
PMID: 30883606 DOI: 10.1371/journal.ppat.1007684
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.