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

Sci Adv. 2022 May 13;8(19):eabh2332. doi: 10.1126/sciadv.abh2332.

Lin Liu ¹ ², Jarrod J Sandow ¹ ², Deena M Leslie Pedrioli ³, Andre L Samson ¹ ², Natasha Silke ¹, Tobias Kratina ¹, Rebecca L Ambrose ⁴ ⁵, Marcel Doerflinger ¹ ², Zhaoqing Hu ¹, Emma Morrish ¹ ², Diep Chau ¹, Andrew J Kueh ¹ ², Cheree Fitzibbon ¹ ², Marc Pellegrini ¹ ², Jaclyn S Pearson ⁴ ⁵ ⁶, Michael O Hottiger ³, Andrew I Webb ¹ ², Najoua Lalaoui ¹ ², John Silke ¹ ²

Affiliations

1 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
2 Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
3 Department of Molecular Mechanisms of Disease (DMMD), University of Zurich, 8057 Zürich, Switzerland.
4 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
5 Department of Molecular and Translational Research, Monash University, Clayton, VIC, Australia.
6 Department of Microbiology, Monash University, Clayton, VIC, Australia.

PMID: 35544574 DOI: 10.1126/sciadv.abh2332

Abstract

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.

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