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Cell Rep. 2014 Aug 7;8(3):883-96. doi: 10.1016/j.celrep.2014.06.044. Epub 2014 Jul 24.

A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis.

Author information

1
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin 10117, Germany.
2
Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, London NW7 1AA, UK.
3
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.

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.

PMID:
25066128
PMCID:
PMC4471680
DOI:
10.1016/j.celrep.2014.06.044
[Indexed for MEDLINE]
Free PMC Article

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