ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway

Cell death induced by tumor necrosis factor (TNF) can be beneficial during infection by helping to mount proper immune responses. However, TNF-induced death can also drive a variety of inflammatory pathologies. Protectives brakes, or cell-death checkpoints, normally repress TNF cytotoxicity to protect the organism from its potential detrimental consequences. Thus, although TNF can kill, this only occurs when one of the checkpoints is inactivated. Here, we describe a checkpoint that prevents apoptosis through the detoxification of the cytotoxic complex IIa that forms upon TNF sensing. We found that autophagy-related 9A (ATG9A) and 200kD FAK family kinase-interacting protein (FIP200) promote the degradation of this complex through a light chain 3 (LC3)–independent lysosomal targeting pathway. This detoxification mechanism was found to counteract TNF receptor 1 (TNFR1)–mediated embryonic lethality and inflammatory skin disease in mouse models. Description A path to prevent TNF cytotoxicity Tumor necrosis factor (TNF) is a central cytokine in inflammatory reactions and is a pharmacological target in several inflammatory disorders. Recent studies demonstrated that the pathological role of TNF in these diseases can originate from its ability to trigger cell death, an outcome that is normally actively repressed in cells. Huyghe et al. identified an unconventional lysosomal targeting process that prevents TNF cytotoxicity by degrading the caspase-8–activating complex that forms in response to TNF binding to TNF receptor 1 (TNFR1). Abrogating this detoxification mechanism caused TNFR1-mediated embryonic lethality or an inflammatory skin disease when locally inactivated in mice. —SMH ATG9A promotes the LC3-independent lysosomal detoxification of the cytotoxic complex IIa to prevent TNF-induced apoptosis.