Department of Pathology, Albert Einstein College of Medicine, New York 10461, USA.
Nat Commun. 2012 Mar 27;3:755. doi: 10.1038/ncomms1754.
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.
内体功能取决于细胞器限制膜的完整性，破坏该膜会引发炎症和细胞死亡。在这里，我们表明，超高相对分子质量聚乙烯颗粒的吞噬作用会损伤内体限制膜，并导致组织蛋白酶漏入细胞质和 NLRP3 炎性体激活。通过二维 DIGE 蛋白质分析、内体分离、内源性和 Annexin A2-GFP 转染细胞的共焦分析以及免疫金标记显示 Annexin A2 募集到受损细胞器。使用荧光脂质体的结合实验证实 Annexin A2 募集到含有吞噬的聚乙烯颗粒的内体。最后，在用聚乙烯颗粒处理后，从 Annexin A2 缺失小鼠的树突状细胞中可以看到细胞质组织蛋白酶、NLRP3 炎性体激活和 IL-1 的产生增加。综上所述，这些结果表明 Annexin A2 与细胞器不稳定后结合到内体膜上具有功能作用。
