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Updated: Mar 2, 2026
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
Initiation and execution mechanisms of necroptosis: an overview
Sasker Grootjans1,2, Tom Vanden Berghe1,2, Peter Vandenabeele1,2
1Molecular Signaling and Cell Death unit, VIB Inflammation Research Center, 9000 Ghent, Belgium.
Abstract:
Necroptosis is a form of regulated cell death, which is induced by ligand binding to TNF family death domain receptors, pattern recognizing receptors and virus sensors. The common feature of these receptor systems is the implication of proteins, which contain a receptor interaction protein kinase (RIPK) homology interaction motif (RHIM) mediating recruitment and activation of receptor-interacting protein kinase 3 (RIPK3), which ultimately activates the necroptosis executioner mixed lineage kinase domain-like (MLKL). In case of the TNF family members, the initiator is the survival- and cell death-regulating RIPK1 kinase, in the case of Toll-like receptor 3/4 (TLR3/4), a RHIM-containing adaptor, called TRIF, while in the case of Z-DNA-binding protein ZBP1/DAI, the cytosolic viral sensor itself contains a RHIM domain. In this review, we discuss the different protein complexes that serve as nucleation platforms for necroptosis and the mechanism of execution of necroptosis. Transgenic models (knockout, kinase-dead knock-in) and pharmacologic inhibition indicate that RIPK1, RIPK3 or MLKL are implicated in many inflammatory, degenerative and infectious diseases. However, the conclusion of necroptosis being solely involved in the etiology of diseases is blurred by the pleiotropic roles of RIPK1 and RIPK3 in other cellular processes such as apoptosis and inflammasome activation.
Insights
Necroptosis, a regulated cell death pathway, involves RIPK1, RIPK3, and MLKL proteins. These are crucial in inflammatory and infectious diseases, though their roles in other cell processes complicate disease association.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Necroptosis is a regulated form of cell death triggered by various receptors.
- Key signaling molecules include receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL).
- These molecules assemble into nucleation platforms to execute cell death.
Purpose of the Study:
- To review the protein complexes involved in necroptosis nucleation.
- To elucidate the molecular mechanisms of necroptosis execution.
- To discuss the role of necroptosis in various diseases.
Main Methods:
- Review of existing literature on necroptosis signaling pathways.
- Analysis of data from transgenic models (knockout, kinase-dead knock-in).
- Examination of results from pharmacologic inhibition studies.
Main Results:
- Necroptosis involves RHIM-dependent recruitment and activation of RIPK3, leading to MLKL activation.
- RIPK1, RIPK3, and MLKL are implicated in inflammatory, degenerative, and infectious diseases.
- The precise role of necroptosis in disease etiology is complex due to RIPK1 and RIPK3's involvement in apoptosis and inflammasome activation.
Conclusions:
- Necroptosis is a critical cell death pathway with diverse inducers and a conserved execution mechanism.
- RIPK1, RIPK3, and MLKL are central players in necroptosis and disease pathogenesis.
- Further research is needed to untangle the specific contributions of necroptosis to disease given the pleiotropic functions of its key regulators.
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