Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis

Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/repe...

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Bibliographic Details
Published in:The FEBS journal 2023-01, Vol.290 (1), p.37-54
Main Authors: Karlowitz, Rebekka, Wijk, Sjoerd J. L.
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - physiology
Cell Death
deubiquitinating enzymes
Humans
Inflammation
Ischemia
MLKL
Mortality
Necroptosis
Phosphorylation
programmed cell death
Protein Kinases - genetics
Protein Kinases - metabolism
Receptor-Interacting Protein Serine-Threonine Kinases - genetics
Reperfusion
RIPK3
Rupture
Ubiquitination
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Summary:Lytic forms of programmed cell death, like necroptosis, are characterised by cell rupture and the release of cellular contents, often provoking inflammatory responses. In the recent years, necroptosis has been shown to play important roles in human diseases like cancer, infections and ischaemia/reperfusion injury. Coordinated interactions between RIPK1, RIPK3 and MLKL lead to the formation of a dedicated death complex called the necrosome that triggers MLKL‐mediated membrane rupture and necroptotic cell death. Necroptotic cell death is tightly controlled by post‐translational modifications, among which especially phosphorylation has been characterised in great detail. Although selective ubiquitination is relatively well‐explored in the early initiation stages of necroptosis, the mechanisms and functional consequences of RIPK3 and MLKL ubiquitination for necrosome function and necroptosis are only starting to emerge. This review provides an overview on how site‐specific ubiquitination of RIPK3 and MLKL regulates, fine‐tunes and reverses the execution of necroptotic cell death. Necroptosis is a type of programmed cell death characterized by the activation of RIPK1 and RIPK3 ultimately leading to MLKL‐mediated membrane rupture. While the roles of RIPK3 and MLKL phosphorylation in necroptosis are well‐studied, the significance of site‐selective ubiquitination of RIPK3 and MLKL in necroptosis still remains enigmatic. This review aims to provide an overview of RIPK3 and MLKL ubiquitination in the control of necroptosis.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.16255