Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 15, Build. 3, 3rd floor, room 439, 2100 Copenhagen O, Denmark.
Sci Adv. 2023 Jun 9;9(23):eadd4977. doi: 10.1126/sciadv.add4977.
It is well established that tumor necrosis factor (TNF) plays an instrumental role in orchestrating the metabolic disorders associated with late stages of cancers. However, it is not clear whether TNF/TNF receptor (TNFR) signaling controls energy homeostasis in healthy individuals. Here, we show that the highly conserved Drosophila TNFR, Wengen (Wgn), is required in the enterocytes (ECs) of the adult gut to restrict lipid catabolism, suppress immune activity, and maintain tissue homeostasis. Wgn limits autophagy-dependent lipolysis by restricting cytoplasmic levels of the TNFR effector, TNFR-associated factor 3 (dTRAF3), while it suppresses immune processes through inhibition of the dTAK1/TAK1-Relish/NF-κB pathway in a dTRAF2-dependent manner. Knocking down dTRAF3 or overexpressing dTRAF2 is sufficient to suppress infection-induced lipid depletion and immune activation, respectively, showing that Wgn/TNFR functions as an intersection between metabolism and immunity allowing pathogen-induced metabolic reprogramming to fuel the energetically costly task of combatting an infection.
众所周知，肿瘤坏死因子（TNF）在协调与癌症晚期相关的代谢紊乱方面发挥着重要作用。然而，目前尚不清楚 TNF/TNF 受体（TNFR）信号是否控制健康个体的能量稳态。在这里，我们表明高度保守的果蝇 TNFR，Wengen（Wgn），在成年肠道的肠细胞（ECs）中是必需的，以限制脂质分解代谢、抑制免疫活性和维持组织稳态。Wgn 通过限制 TNFR 效应物 TNFR 相关因子 3（dTRAF3）的细胞质水平来限制自噬依赖性脂肪分解，同时通过 dTAK1/TAK1-Relish/NF-κB 途径抑制免疫过程，这是一种依赖于 dTRAF2 的方式。敲低 dTRAF3 或过表达 dTRAF2 足以分别抑制感染诱导的脂质耗竭和免疫激活，表明 Wgn/TNFR 作为代谢和免疫之间的交点，允许病原体诱导的代谢重编程为对抗感染的能量密集任务提供燃料。
