PLoS Pathogens (Mar 2019)

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

  • Astrid Skjesol,
  • Mariia Yurchenko,
  • Korbinian Bösl,
  • Caroline Gravastrand,
  • Kaja Elisabeth Nilsen,
  • Lene Melsæther Grøvdal,
  • Federica Agliano,
  • Francesco Patane,
  • Germana Lentini,
  • Hera Kim,
  • Giuseppe Teti,
  • Aditya Kumar Sharma,
  • Richard K Kandasamy,
  • Bjørnar Sporsheim,
  • Kristian K Starheim,
  • Douglas T Golenbock,
  • Harald Stenmark,
  • Mary McCaffrey,
  • Terje Espevik,
  • Harald Husebye

DOI
https://doi.org/10.1371/journal.ppat.1007684
Journal volume & issue
Vol. 15, no. 3
p. e1007684

Abstract

Read online

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.