Title | Annexin A2 binds to endosomes following organelle destabilization by particulate wear debris. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Scharf B, Clement CC, Wu X-X, Morozova K, Zanolini D, Follenzi A, Larocca JN, Levon K, Sutterwala FS, Rand J, Cobelli N, Purdue E, Hajjar KA, Santambrogio L |
Journal | Nat Commun |
Volume | 3 |
Pagination | 755 |
Date Published | 2012 Mar 27 |
ISSN | 2041-1723 |
Keywords | Animals, Annexin A2, Carrier Proteins, Cathepsins, Dendritic Cells, Endosomes, Green Fluorescent Proteins, Humans, Inflammasomes, Interleukin-1, Intracellular Membranes, Joint Prosthesis, Liposomes, Mice, Mice, Inbred C57BL, Mice, Knockout, Microspheres, NLR Family, Pyrin Domain-Containing 3 Protein, Phagocytosis, Polyethylenes |
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. |
DOI | 10.1038/ncomms1754 |
Alternate Journal | Nat Commun |
PubMed ID | 22453828 |
Grant List | R01 HL 090895 / HL / NHLBI NIH HHS / United States R01 HL 042493 / HL / NHLBI NIH HHS / United States |
Related Faculty:
Jacob H. Rand, M.D.