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Updated: Jun 4, 2025
Author Spotlight: THP-1 Macrophage Response to LPS/ATP — Unveiling the Pyroptosis, Apoptosis, and Necroptosis Spectrum
Published on: May 3, 2024
Protein shapeshifting in necroptotic cell death signaling
Hanadi Hoblos1, Wayne Cawthorne1, André L Samson1
1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
Abstract:
Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors - Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL - can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux. As molecular level knowledge of cell death signaling grows, we anticipate targeting the conformations of key necrosomal effector proteins will emerge as new avenues for drug development.
Insights
Necroptosis, a programmed cell death pathway, is regulated by protein assembly and modifications. Targeting these key effector proteins offers new therapeutic strategies for inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Necroptosis is a programmed cell death pathway crucial in innate immunity.
- Dysregulation of necroptosis is implicated in various inflammatory diseases.
- Key effectors include Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL.
Purpose of the Study:
- To explore how protein conformation and assembly of necroptosis effectors are modulated.
- To investigate the role of post-translational modifications and intermolecular interactions in necroptosis.
- To identify potential therapeutic targets within the necroptosis pathway.
Main Methods:
- Analysis of protein conformation and higher-order assembly of ZBP1, RIPK1, RIPK3, and MLKL.
- Investigation of post-translational modifications (phosphorylation, ubiquitylation, lipidation).
- Examination of intermolecular interactions influencing necroptotic signaling flux.
Main Results:
- Protein conformation and assembly of necroptosis effectors are dynamically regulated.
- Post-translational modifications and intermolecular interactions fine-tune necroptotic signaling.
- Specific molecular mechanisms controlling necroptosis pathway activity were elucidated.
Conclusions:
- Modulating protein conformation of key necroptosis effectors is a promising therapeutic strategy.
- Targeting necroptosis pathway components offers potential for treating inflammatory diseases.
- Advancing molecular understanding of cell death signaling opens new drug development avenues.
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