Annexin A2 binds to endosomes following organelle destabilization by particulate wear debris

Nat Commun. 2012 Mar 27;3:755. doi: 10.1038/ncomms1754.

Abstract

Endosomal functions are contingent on the integrity of the organelle-limiting membrane, whose disruption induces inflammation and cell death. Here we show that phagocytosis of ultrahigh molecular weight polyethylene particles induces damage to the endosomal-limiting membrane and results in the leakage of cathepsins into the cytosol and NLRP3-inflammasome activation. Annexin A2 recruitment to damaged organelles is shown by two-dimensional DIGE protein profiling, endosomal fractionation, confocal analysis of endogenous and annexin A2-GFP transfected cells, and immunogold labelling. Binding experiments, using fluorescent liposomes, confirms annexin A2 recruitment to endosomes containing phagocytosed polyethylene particles. Finally, an increase in cytosolic cathepsins, NLRP3-inflammasome activation, and IL-1 production is seen in dendritic cells from annexin A2-null mice, following exposure to polyethylene particles. Together, the results indicate a functional role of annexin A2 binding to endosomal membranes following organelle destabilization.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A2 / genetics
  • Annexin A2 / metabolism*
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / metabolism*
  • Cathepsins / metabolism*
  • Dendritic Cells / metabolism
  • Endosomes / metabolism
  • Green Fluorescent Proteins / genetics
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1 / biosynthesis
  • Intracellular Membranes / metabolism
  • Intracellular Membranes / ultrastructure*
  • Joint Prosthesis
  • Liposomes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microspheres
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phagocytosis*
  • Polyethylenes

Substances

  • Annexin A2
  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1
  • Liposomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Polyethylenes
  • ultra-high molecular weight polyethylene
  • Green Fluorescent Proteins
  • Cathepsins