A20 and Cell Death-driven Inflammation

A20 is a ubiquitin-modulating enzyme that harbors both E3 ligase and deubiquitylase activities. In addition, it contains specialized ubiquitin-binding domains (ZnF domains) to regulate innate immune signaling pathways. Mutations in TNFAIP3, the gene encoding A20, are associated with various inflammatory disorders, such as Crohn's disease, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, psoriasis, and atherosclerosis. The anti-inflammatory properties of A20 were long attributed to its ability to inhibit NF-κB signaling. Recent studies in the mouse demonstrate that A20 indirectly prevents pathological inflammation by inhibiting cell death. A20 protects cells from apoptosis, necroptosis, pyroptosis, or a combination of these cell death modalities, depending on the cellular context. To protect cells from death, A20 can combine both its catalytic and nonenzymatic activities. A20 is a potent anti-inflammatory molecule, and mutations in TNFAIP3, the gene encoding A20, are associated with a wide panel of inflammatory pathologies, both in human and mouse. The anti-inflammatory properties of A20 are commonly attributed to its ability to suppress inflammatory NF-κB signaling by functioning as a ubiquitin-editing enzyme. However, A20 also protects cells from death, independently of NF-κB regulation, and recent work has demonstrated that cell death may drive some of the inflammatory conditions caused by A20 deficiency. Adding to the fact that the protective role of A20 does not primarily rely on its catalytic activities, these findings shed new light on A20 biology. A20 is a potent anti-inflammatory molecule, and mutations in TNFAIP3, the gene encoding A20, are associated with a wide panel of inflammatory pathologies, both in human and mouse. The anti-inflammatory properties of A20 are commonly attributed to its ability to suppress inflammatory NF-κB signaling by functioning as a ubiquitin-editing enzyme. However, A20 also protects cells from death, independently of NF-κB regulation, and recent work has demonstrated that cell death may drive some of the inflammatory conditions caused by A20 deficiency. Adding to the fact that the protective role of A20 does not primarily rely on its catalytic activities, these findings shed new light on A20 biology. CARD-containing inflammasome adaptor protein that connects the NLR receptor with the proinflammatory Caspase-1. metabolic syndrome characterized by muscle mass loss. crucial E3 ligases in the TNFR1 signaling pathway required for MAPK/NF-κB activation. TNFR1-associated multiprotein complex that mediates TNF-induced MAPK/NF-κB activation. cytosolic multiprotein complexes that mediate TNF-induced apoptosis and necroptosis. cytosolic and RHIM-containing Z-DNA/RNA sensor that has the ability to induce apoptosis and necroptosis. molecules that are released by dying cells to alert the immune system. mediators of pyroptotic cell death. They contain a pore-forming N-terminal domain that is unleashed upon cleavage by caspases. a multifunctional protein that serves as a transcriptional regulator in the nucleus but, upon secretion, acts as a DAMP, potently inducing inflammation. large multiprotein complex(es) that generally contain an NLR protein and the inflammatory Caspase-1; facilitate pyroptosis induction and IL-18 and IL-1β maturation and release. 3D microcultures of the small intestinal epithelium layer. heterotrimeric E3 ligase (comprising HOIP, HOIL-1, and SHARPIN) able to specifically generate linear (M1) ubiquitin chains. adaptor protein for both canonical IKKα/β and noncanonical IKKε/TBK1 kinase complexes; binds M1-ubiquitin chains and facilitates IKK recruitment to immune signaling complexes. bacterial components recognized by the immune system that trigger inflammation. family of pattern recognition receptors that sense a variety of extracellular and intracellular microbial components.