The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils
Details
Publication Year 2018-09-04, Volume 11, Issue #546, Page eaao1716
Journal Title
Science Signaling
Publication Type
Journal Article
Abstract
Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain-like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase-independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8-dependent apoptotic or RIPK3/MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8-dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.
Publisher
AAAS
WEHI Research Division(s)
Inflammation
PubMed ID
30181240
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-09-07 02:34:57
Last Modified: 2018-09-07 02:40:37
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