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

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.

Source: Signal Transduction Knowledge Environment - September 4, 2018 Category: Science Authors: DCruz, A. A., Speir, M., Bliss-Moreau, M., Dietrich, S., Wang, S., Chen, A. A., Gavillet, M., Al-Obeidi, A., Lawlor, K. E., Vince, J. E., Kelliher, M. A., Hakem, R., Pasparakis, M., Williams, D. A., Ericsson, M., Croker, B. A. Tags: STKE Research Articles Source Type: news