A Myeloperoxidase-Containing Complex Regulates Neutrophil Elastase Release and Actin Dynamics during NETosis

Summary

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.

Graphical Abstract

Highlights

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  A complex of antimicrobials drives neutrophil elastase to the nucleus during NETosis

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  The “azurosome” complex mediates protein release across intact membranes

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  Myeloperoxidase is required for neutrophil elastase release

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  Neutrophil elastase degrades F-actin and arrests actin dynamics

Abstract

Neutrophils combat pathogens by releasing decondensed web-like chromatin structures called neutrophil extracellular traps (NETs). During NET formation, a protease called neutrophil elastase (NE), which is stored in subcellular membrane compartments called granules, translocates to the nucleus, cleaving histones to promote chromatin decondensation. Metzler et al. show that a complex of antimicrobial proteins named “azurosome” mediates NE release in response to reactive oxygen species independently of membrane fusion and without disrupting membrane integrity, while activating NE to degrade F-actin and arrest actin dynamics.