Bilirubin directly activates RIPK3 to induce non-classical necroptosis
Qian Xue, Xi Ma, Ziyuan Chen, Feifei Ge, Jiawen Wu, Wenhao Bao, Li Zhou, Wei Yi, Min Wu, Siyan Liao, Wenwen Xu, Rongrong He, Jingcheng Feng, Yameng Hu, Xi Chen, Xintian Wu, Ding Yan, Daolin Tang, Xin Chen, Jinbao Liu
TL;DR
Bilirubin, known for antioxidant properties, was found to activate RIPK3 and cause neurotoxicity through a non-classical necroptosis pathway.
Contribution
The study reveals a novel, RIPK1-independent mechanism of RIPK3 activation by bilirubin, leading to non-canonical necroptosis.
Findings
Bilirubin directly binds to RIPK3 residues D161 and S102, triggering its oligomerization and autophosphorylation.
Bilirubin-induced necroptosis does not require the RHIM domain of RIPK3 or other RHIM-containing proteins.
Depletion of Ripk3 reduces bilirubin-induced neurotoxicity in mouse models.
Abstract
Bilirubin, a byproduct of heme metabolism, is traditionally recognized for its antioxidant properties. However, its accumulation under pathological conditions can result in severe clinical manifestations, including neurotoxicity. Here, we report that bilirubin acts as an activator of receptor-interacting protein kinase 3 (RIPK3), inducing necroptosis and contributing to neurotoxic effects. Unlike the canonical pathway, in which RIPK3-mediated necroptosis is dependent on RIPK1, bilirubin directly binds to the D161 and S102 residues within the kinase domain of RIPK3. This binding facilitates RIPK3 oligomerization and autophosphorylation, leading to the activation of MLKL, the primary effector of necroptosis. Notably, bilirubin-induced necroptosis does not require the RHIM domain of RIPK3 or other RHIM-containing proteins, such as ZBP1 and TRIF. Functionally, the depletion of Ripk3 reduces…
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Taxonomy
TopicsHeme Oxygenase-1 and Carbon Monoxide · Cell death mechanisms and regulation · Neonatal Health and Biochemistry