| First Author | D'Cruz AA | Year | 2018 |
| Journal | Sci Signal | Volume | 11 |
| Issue | 546 | PubMed ID | 30181240 |
| Mgi Jnum | J:281925 | Mgi Id | MGI:6380838 |
| Doi | 10.1126/scisignal.aao1716 | Citation | D'Cruz AA, et al. (2018) The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils. Sci Signal 11(546) |
| abstractText | 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. |
