Format

Send to

Choose Destination
Sci Signal. 2018 Sep 4;11(546). pii: eaao1716. doi: 10.1126/scisignal.aao1716.

The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils.

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.
2
Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Hematology, Lausanne University Hospital, 1011 Lausanne, Switzerland.
4
Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Parkville 3052, Australia.
5
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
6
Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
7
Institute for Genetics, Center for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50931 Cologne, Germany.
8
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
9
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA. ben.croker@childrens.harvard.edu.

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.

PMID:
30181240
PMCID:
PMC6301070
DOI:
10.1126/scisignal.aao1716
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center