MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction by Zhangcheng Ding & Rui Wang & Yuhua Li & Xiaodong Wang instant download

MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction by Zhangcheng Ding & Rui Wang & Yuhua Li & Xiaodong Wang instant download

SUMMARYNecroptosis is a pro-inflammatory, lytic cell death executed by a pseudokinase mixed lineage kinase-likeprotein MLKL. Upon necroptosis induction by various inflammatory signals, MLKL is phosphorylated by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and translocates from the cytosol to the plasmamembrane, causing membrane disruption and the release of damage-associated molecular patterns(DAMPs). We report here that phosphor-MLKL also translocates to mitochondria and induces a microtubule-dependent release of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, resulting in the upregulation of interferonbeta (Ifnb) expression. In a necroptosis-mediated inflammatory bowel disease (IBD) mouse model, interferingwith the cGAS-STING pathway reduced inflammation and promoted intestinal recovery. Thus, MLKL inducesinflammation not only in a cell non-autonomous fashion by releasing DAMP signals, but also in a cell-autonomous manner by causing mtDNA leakage into the cytosol, thereby activating the cGAS-STING pathway.