比利时根特大学
研究人员描述了一个检查点，它通过解毒TNF感应时形成的细胞毒性复合物IIa来防止细胞凋亡。研究人员发现自噬相关的9A（ATG9A）和200kD FAK家族激酶相互作用蛋白（FIP200）通过与轻链3（LC3）无关的溶酶体靶向途径促进该复合物的降解。这种解毒机制被发现可以对抗TNF受体1（TNFR1）介导的胚胎死亡和小鼠模型中的炎症性皮肤病。
据介绍，TNF诱导的细胞死亡在感染期间可以通过帮助启动适当的免疫反应而获益。然而，TNF诱导的死亡也可以驱动各种炎症性病变。保护性刹车，或细胞死亡检查点，通常会抑制TNF的细胞毒性，从而保护机体免受其潜在的有害后果。因此，尽管TNF可以杀伤，但这只发生在其中一个检查点失活的时候。
附：英文原文
Title: ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway
Author: Jon Huyghe, Dario Priem, Lisette Van Hove, Barbara Gilbert, Jürgen Fritsch, Yasuo Uchiyama, Esther Hoste, Geert van Loo, Mathieu J. M. Bertrand
Issue&Volume: 2022-12-16
Abstract: 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.
DOI: add6967
Source: https://www.science.org/doi/10.1126/science.add6967