title: A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis.
abstract: Neutrophils contain granules loaded with antimicrobial proteins and are regarded as impermeable organelles that deliver cargo via membrane fusion. However, during the formation of neutrophil extracellular traps (NETs), neutrophil elastase (NE) translocates from the granules to the nucleus via an unknown mechanism that does not involve membrane fusion and requires reactive oxygen species (ROS). Here, we show that the ROS triggers the dissociation of NE from a membrane-associated complex into the cytosol and activates its proteolytic activity in a myeloperoxidase (MPO)-dependent manner. In the cytosol, NE first binds and degrades F-actin to arrest actin dynamics and subsequently translocates to the nucleus. The complex is an example of an oxidative signaling scaffold that enables ROS and antimicrobial proteins to regulate neutrophil responses. Furthermore, granules contain protein machinery that transports and delivers cargo across membranes independently of membrane fusion.
authors: Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin 10117, Germany.
authors: Kathleen D
authors: KD
authors: Metzler
authors: Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin 10117, Germany.
authors: Christian
authors: C
authors: Goosmann
authors: Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, London NW7 1AA, UK.
authors: Aleksandra
authors: A
authors: Lubojemska
authors: Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin 10117, Germany.
authors: Arturo
authors: A
authors: Zychlinsky
authors: Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin 10117, Germany; Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, London NW7 1AA, UK. Electronic address: vpapaya@nimr.mrc.ac.uk.
authors: Venizelos
authors: V
authors: Papayannopoulos
mesh_terms: D000199:Actins / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D065206:Extracellular Traps / Q000378:metabolism*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism*; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000199:Actins; D017382:Reactive Oxygen Species; D009195:Peroxidase; D019272:Leukocyte Elastase