M. tuberculosis-Initiated Human Mannose Receptor Signaling Regulates Macrophage Recognition and Vesicle Trafficking by FcRγ-Chain, Grb2, and SHP-1

Cell Rep. 2017 Oct 3;21(1):126-140. doi: 10.1016/j.celrep.2017.09.034.

Abstract

Despite its prominent role as a C-type lectin (CTL) pattern recognition receptor, mannose receptor (MR, CD206)-specific signaling molecules and pathways are unknown. The MR is highly expressed on human macrophages, regulating endocytosis, phagocytosis, and immune responses and mediating Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages, thereby limiting phagosome-lysosome (P-L) fusion. We identified human MR-associated proteins using phosphorylated and non-phosphorylated MR cytoplasmic tail peptides. We found that MR binds FcRγ-chain, which is required for MR plasma membrane localization and M.tb cell association. Additionally, we discovered that MR-mediated M.tb association triggers immediate MR tyrosine residue phosphorylation and Grb2 recruitment, activating the Rac/Pak/Cdc-42 signaling cascade important for M.tb uptake. MR activation subsequently recruits SHP-1 to the M.tb-containing phagosome, where its activity limits PI(3)P generation at the phagosome and M.tb P-L fusion and promotes M.tb growth. In sum, we identify human MR signaling pathways that temporally regulate phagocytosis and P-L fusion during M.tb infection.

Keywords: C-type lectin; Mycobacterium; human macrophage; lysosome; mannose receptor; phagosome; tuberculosis.

MeSH terms

  • GRB2 Adaptor Protein / genetics*
  • GRB2 Adaptor Protein / metabolism
  • Gene Expression Regulation
  • Host-Pathogen Interactions*
  • Humans
  • Lectins, C-Type / genetics*
  • Lectins, C-Type / metabolism
  • Lysosomes / metabolism
  • Lysosomes / microbiology
  • Macrophages / metabolism*
  • Macrophages / microbiology
  • Mannose Receptor
  • Mannose-Binding Lectins / genetics*
  • Mannose-Binding Lectins / metabolism
  • Membrane Fusion
  • Mycobacterium tuberculosis / growth & development
  • Mycobacterium tuberculosis / metabolism*
  • Phagocytosis / genetics
  • Phagosomes / metabolism
  • Phagosomes / microbiology
  • Phosphorylation
  • Primary Cell Culture
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Receptors, IgG / genetics*
  • Receptors, IgG / metabolism
  • Signal Transduction
  • Transport Vesicles / metabolism
  • Transport Vesicles / microbiology
  • Tyrosine / metabolism
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism

Substances

  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Lectins, C-Type
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Receptors, Cell Surface
  • Receptors, IgG
  • Tyrosine
  • p21-Activated Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein
  • rac GTP-Binding Proteins