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.