Liu Lin, Sandow Jarrod J, Leslie Pedrioli Deena M, Samson Andre L, Silke Natasha, Kratina Tobias, Ambrose Rebecca L, Doerflinger Marcel, Hu Zhaoqing, Morrish Emma, Chau Diep, Kueh Andrew J, Fitzibbon Cheree, Pellegrini Marc, Pearson Jaclyn S, Hottiger Michael O, Webb Andrew I, Lalaoui Najoua, Silke John
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Sci Adv. 2022 May 13;8(19):eabh2332. doi: 10.1126/sciadv.abh2332. Epub 2022 May 11.
Tumor necrosis factor (TNF) is a key component of the innate immune response. Upon binding to its receptor, TNFR1, it promotes production of other cytokines via a membrane-bound complex 1 or induces cell death via a cytosolic complex 2. To understand how TNF-induced cell death is regulated, we performed mass spectrometry of complex 2 and identified tankyrase-1 as a native component that, upon a death stimulus, mediates complex 2 poly-ADP-ribosylation (PARylation). PARylation promotes recruitment of the E3 ligase RNF146, resulting in proteasomal degradation of complex 2, thereby limiting cell death. Expression of the ADP-ribose-binding/hydrolyzing severe acute respiratory syndrome coronavirus 2 macrodomain sensitizes cells to TNF-induced death via abolishing complex 2 PARylation. This suggests that disruption of ADP-ribosylation during an infection can prime a cell to retaliate with an inflammatory cell death.
肿瘤坏死因子（TNF）是先天性免疫反应的关键组成部分。与受体TNFR1结合后，它通过膜结合复合物1促进其他细胞因子的产生，或通过胞质复合物2诱导细胞死亡。为了解TNF诱导的细胞死亡是如何被调控的，我们对复合物2进行了质谱分析，并鉴定出端锚聚合酶-1是一种天然成分，在死亡刺激下，它介导复合物2的多聚ADP核糖基化（PARylation）。PARylation促进E3连接酶RNF146的募集，导致复合物2的蛋白酶体降解，从而限制细胞死亡。ADP核糖结合/水解严重急性呼吸综合征冠状病毒2大结构域的表达通过消除复合物2的PARylation使细胞对TNF诱导的死亡敏感。这表明感染期间ADP核糖基化的破坏可使细胞准备以炎症性细胞死亡进行反击。
