A20 is a negative regulator of both NF-κB and JNK signaling following T cell receptor stimulation in humans

Abstract A20 is an NF-κB-induced, dual function ubiquitin editing enzyme that negatively regulates NF-κB signaling induced by TNF and other innate immune receptors, constraining inflammation. Indeed, haploinsufficiency drives a severe autoinflammatory disease in humans. Although serves similar negative feedback for T cell receptor (TCR) signaling, the molecular mechanisms utilized their ultimate impact on human remain unclear. TCR engagement triggers assembly of CARD11-BCL10-MALT1 (CBM) protein complex, platform governs activation downstream transcription factors including c-Jun. We employed extensive set mutant expression constructs to better elucidate how output Jurkat cells. Intriguingly, knockout cells showed enhanced, sustained JNK after stimulation, which was reversed upon wild-type (WT) complementation. deubiquitinase entirely dispensable regulation, whereas zinc finger domains confer E3 ligase activity (ZnF4) linear ubiquitin-binding capacity (ZnF7) were required. Abolishing MALT1-dependent proteolytic cleavage did not affect suppressive function, although neither N- nor C-terminal fragments retained regulatory capacity. also found CRISPR-mediated deletion adversely affects survival expansion primary Ongoing studies will determine effector responses decipher dysregulated and/or contributes cell-intrinsic abnormalities perturb adaptive homeostasis.