Insane in the membrane: a structural perspective of MLKL function in necroptosis. Issue 2 (17th January 2017) - Petrie, Emma J
Abstract : Necroptosis (or 'programmed necrosis') is a caspase‐independent cell death pathway that operates downstream of death receptors, including Tumour Necrosis Factor Receptor‐1 (TNFR1), and the Toll‐like receptors, TLR3 and TLR4. Owing to its immunogenicity, necroptosis has been attributed roles in the pathogenesis of several diseases, including inflammatory bowel disease and the tissue damage arising from ischaemic‐reperfusion injuries. Only over the past 7 years has the core machinery of this pathway, the receptor‐interacting protein kinase‐3 (RIPK3) and the pseudokinase, Mixed Lineage Kinase domain‐Like (MLKL), been defined. Our current understanding of the pathway is that RIPK3‐mediated phosphorylation activates cytoplasmic MLKL, which is the most terminal known effector in the pathway, leading to MLKL's oligomerisation, translocation to, and permeabilisation of, the plasma membrane. Here, we discuss the insights gleaned from structural and biophysical studies of MLKL and highlight the known unknowns surrounding MLKL's mechanism of action and activation. Abstract : The February 2017 issue contains a Special Feature on Necroptotic death signalling: evolution, mechanisms and disease relevance. In recent years, research into a genetically encoded cell death program termed necroptosis has accelerated into vogue. Many laboratories are now racing to answer key questions such as: How does it occur? When does it occur? What does it do? What is it good (or not so good) for? Answers to these will ultimately guide efforts aimed at manipulating this new pathway for therapeutic benefit. In the six articles in this ICB Special Feature, the current state of play in necroptotic cell death research is dissected in considerable detail. The articles provide timely updates on what we have learnt so far and, importantly, where we might be going. Immunology & Cell Biology thanks the coordinator of this Special Feature ‐ James Vince ‐ for his planning and input.