Tankyrase-mediated ADP-ribosylation is a novel regulator of TNF-induced death

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. Intriguingly, expression of the ADP-ribose binding/hydrolyzing SARS-CoV-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.