title: Annexin A2 binds to endosomes following organelle destabilization by particulate wear debris.
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.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, New York 10461, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Scharf
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Clement
authors.forename: Xiao-Xuan
authors.initials: XX
authors.lastname: Wu
authors.forename: Kateryna
authors.initials: K
authors.lastname: Morozova
authors.forename: Diego
authors.initials: D
authors.lastname: Zanolini
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Jorge N
authors.initials: JN
authors.lastname: Larocca
authors.forename: Kalle
authors.initials: K
authors.lastname: Levon
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.forename: Jacob
authors.initials: J
authors.lastname: Rand
authors.forename: Neil
authors.initials: N
authors.lastname: Cobelli
authors.forename: Ed
authors.initials: E
authors.lastname: Purdue
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis; D007425:Intracellular Membranes / Q000378:metabolism / Q000648:ultrastructure*; D007595:Joint Prosthesis; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008863:Microspheres; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010587:Phagocytosis; D011095:Polyethylenes
chemical_list: D017306:Annexin A2; D002352:Carrier Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D008081:Liposomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011095:Polyethylenes; C111601:ultra-high molecular weight polyethylene; D049452:Green Fluorescent Proteins; D002403:Cathepsins