A novel role of ATG9A and RB1CC1/FIP200 in mediating cell-death checkpoints to repress TNF cytotoxicity.

TNF (tumor necrosis factor) is an important cytokine that regulates immune responses in response to microbial infection. Two fates can be induced by TNF sensing, including activation of NFKB/NF-κB and cell death, which are mainly regulated by the formation of TNFRSF1A/TNFR1 (TNF receptor superfamily member 1A) complex I and complex II, respectively. Abnormal TNF-induced cell death leads to detrimental outcomes, underlying several human inflammatory diseases. The actions of "protective brakes", or so-called specific "cell death checkpoints", are important to prevent TNF cytotoxicity. A recent study published in Science characterizes novel functions of ATG9A, RB1CC1/FIP200 and TAX1BP1 as components of a previously undiscovered TNF-induced cell death checkpoint, independent of its roles in canonical macroautophagy/autophagy. Notably, this ATG9A-controlled cell-death checkpoint contributes to the prevention of inflammatory skin disease, demonstrating its crucial role in serving as a safeguard against the threat of TNF cytotoxicity.