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Tankyrase-mediated ADP-ribosylation is a regulator of TNF-induced death
Lin Liu1,2, Jarrod J Sandow1,2, Deena M Leslie Pedrioli3
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
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.
Insights
Tumor necrosis factor (TNF) regulates cell death through complex 2. Its poly-ADP-ribosylation (PARylation) by tankyrase-1 limits cell death, a process disrupted by SARS-CoV-2, potentially causing inflammatory cell death.
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- Tumor necrosis factor (TNF) is crucial for innate immunity, signaling through TNFR1 to initiate cytokine production or cell death.
- TNF-induced cell death is mediated by cytosolic complex 2, but its regulation remains incompletely understood.
Purpose of the Study:
- To elucidate the regulatory mechanisms governing TNF-induced cell death.
- To identify novel components and pathways involved in complex 2 regulation.
Main Methods:
- Mass spectrometry was employed to analyze the composition of complex 2.
- Poly-ADP-ribosylation (PARylation) assays were performed to assess protein modification.
- Ubiquitin ligase recruitment and proteasomal degradation assays were conducted.
Main Results:
- Tankyrase-1 was identified as a key component of complex 2, mediating its poly-ADP-ribosylation (PARylation).
- PARylation of complex 2 promotes the recruitment of E3 ligase RNF146, leading to proteasomal degradation and limiting cell death.
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain expression inhibited complex 2 PARylation, sensitizing cells to TNF-induced death.
Conclusions:
- Tankyrase-1-mediated PARylation of complex 2 is a critical negative regulator of TNF-induced cell death.
- Disruption of ADP-ribosylation by viral factors, such as SARS-CoV-2, can impair this regulatory mechanism.
- This impairment may lead to heightened inflammatory cell death responses during viral infections.
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