Necroptosis molecular mechanisms: Recent findings regarding novel necroptosis regulators

Abstract

Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic phenotypes, including swelling and membrane rupture, and release damage-associated molecular patterns (DAMPs), inflammatory cytokines, and chemokines, thereby mediating extreme inflammatory responses. Studies on gene knockout or necroptosis-specific inhibitor treatment in animal models have provided extensive evidence regarding the important roles of necroptosis in inflammatory diseases. The necroptosis signaling pathway is primarily modulated by activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates mixed-lineage kinase domain-like protein (MLKL), mediating MLKL oligomerization. In the necroptosis process, these proteins are fine-tuned by posttranslational regulation via phosphorylation, ubiquitination, glycosylation, and protein–protein interactions. Herein, we review recent findings on the molecular regulatory mechanisms of necroptosis.

Inflammation: Understanding cell death opens therapeutic possibilities

A better understanding of the signaling pathways that drive an inflammatory mode of cell death known as necroptosis could lead to new therapies for autoimmune and neuroinflammatory conditions. Necroptosis is a regulated form of cell death often triggered by infections, tissue injuries, and chronic inflammatory conditions. It leads cells to rupture and disperse their contents, which in turn spurs an inflammatory immune response that can sometimes fuel disease. A team from South Korea led by Jaewhan Song of Yonsei University in Seoul discusses the molecular mechanisms of this process. They focus on several key mediators of the necroptosis signaling pathway and how those proteins in turn are modified to regulate their function. Several drug inhibitors of these proteins are already in clinical development for the treatment of psoriasis and other inflammatory disorders.