ADAR1 orchestrates the ZBP1-mediated PANoptosis and heart transplant rejection
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Abstract
Background
PANoptosis is an integrated form of cell death that combines features of pyroptosis, apoptosis, and necroptosis and is regulated by a complex network of signaling proteins. The roles of ADAR1 (adenosine deaminase acting on RNA 1) and RIPK1 (receptor-interacting serine/threonine-protein kinase 1) in orchestrating the ZBP1 (Z-DNA binding protein 1)-RIPK3 complex to mediate PANoptosis is not fully understood, particularly in the context of heart transplantation.
Objective
This study investigated how ADAR1 and RIPK1 coordinate the activation of the ZBP1-RIPK3 complex to mediate PANoptosis and its implications in mouse heart transplantation.
Methods
Using both in vitro and in vivo models, we analyzed the interactions between ADAR1, RIPK1, ZBP1, and RIPK3. We employed western blotting, and siRNA to elucidate the dynamics of these interactions. Additionally, we assessed the impact of ZBP1 on mouse heart transplantation outcomes.
Results
Our studies revealed that ADAR1 regulates the activation of the ZBP1-RIPK3 complex for PANoptosis. The interaction of ADAR1 with ZBP1 protected against Z-DNA-induced cell death by limiting activations of ZBP1 and RIPK3. In mouse heart transplantation study, we found that ZBP1 and its ligand Z-DNA/Z-RNA were significantly increased in the graft post-transplantation. Furthermore, ZBP1 deficiency in the heart graft inhibited cardiac PANoptosis, attenuated acute graft injury, and induced long-term graft survival.
Conclusion
This study elucidates the role of ADAR1 in ZBP1-mediated PANoptosis. Inhibition of ZBP1 can prevent heart graft injury and rejection. Understanding these mechanisms provides valuable insights into the regulation of cell death and may inform the development of novel therapeutic strategies to improve transplant outcomes.
Article activity feed
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Transplant-associated ischemia and reperfusion and subsequent anti-donor immuneresponses result in cell death, tissue injury, and graft rejection. Hence, inhibition of cell death isan appropriate strategy to attenuate organ injury and prolong graft survival
Is PANoptosis and the role of ZBP1/ADAR1 applicable exclusively to heart transplantation, or could this work be extended to transplantation of other organs as well? -
Interestingly, ZBP1 deficiency benefited graft survival compared to wild-type grafts (meansurvival = 128.5 ± 22.6 days vs. 28.8 ± 6.7 days, n = 6, p = 0.00014, Figure 6G)
The increase of graft survival time by nearly 5x is truly exciting. Incredibly impressive! Do you have thoughts on how you might try to translate these findings into the clinic? Is it possible to knock-down ZBP1 in human tissue ex vivo, or to use a molecular inhibitor? -
Immunohistochemistry (IHC) analysis showed significantly increased levels of Z-DNA/RNA inheart grafts 3 days post-transplantation
What is the initial source of cfDNA after transplantation if not PANoptosis? Is this a result of ischemia-reperfusion injury?
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Inaddition, Z-DNA/RNA stimulates ZBP1 or ADAR1 by recognizing the Zα domain
How does ADAR1 inhibit formation of the ZBP1-RIPK3 complex? Does this exclusively involve interaction via Z-alpha domain? Is ADAR1’s RNA-modifying capability dispensable for this effect? It might be interesting to explore a truncated or point-mutant ADAR1 that lacks RNA-deaminating capability to see if its protective effect is preserved. -
Interestingly, each of those inhibitors partially reduced cell death (Figure 2A-B), which was alsoconfirmed by analysis of ATP levels
You show that inhibitors of pyroptosis, apoptosis, and necroptosis reduce cell death in vitro. Have you tried combining all three inhibitors, and if so, does this completely block cell death in response to cfDNA? Have you explored inhibitors of other forms of cell death, such as ferroptosis? -
