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


D'Cruz, AA; Speir, M; Bliss-Moreau, M; Dietrich, S; Wang, S; Chen, AA; Gavillet, M; Al-Obeidi, A; Lawlor, KE; Vince, JE; Kelliher, MA; Hakem, R; Pasparakis, M; Williams, DA; Ericsson, M; Croker, BA
2018-09-04
Science Signaling
Journal Article
11
546
eaao1716
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.
AAAS
Inflammation
10.1126/scisignal.aao1716
30181240
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Creation Date 2018-09-07 02:34:57 Last Modified 2018-09-07 02:40:37