ArticleCell death and differentiation2022
Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL.
Article in Cell death and differentiation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
27 citing papers in PubMed, 39 citations in OpenAlex.
- The kinase domain of RIPK3 tunes its scaffolding functions.Cell death and differentiation · 2026Article
- A non-classical necroptosis pathway mediated by caspases.Cell communication and signaling : CCS · 2026Article
- Species-specific regulation of necroptosis by STK38-dependent RIPK1 phosphorylation.Cell death and differentiation · 2026Article
- Autoinhibitory control of MLKL governs pseudokinase domain phosphorylation and oligomerization during necroptosis.Cell reports · 2026Article
- Targeting MLKL-Driven Necroptosis: A Therapeutic Target in Inflammation and Host Defense.Biomolecules · 2026Review
- Intranasal delivery route for neurodegenerative diseases: recent insights and future directions.Drug delivery and translational research · 2026Review
- To Die or Not to Die: How Sublethal Damage Rewires Cell Fate and Implications for Sepsis.Journal of inflammation research · 2026Review
- Mixed Lineage Kinase Domain-Like Protein (MLKL): From Mechanisms to Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Bypassing the guardian: regulated cell death pathways in p53-mutant cancers.Cellular & molecular biology letters · 2025Review
- Divergent roles of RIPK3 and MLKL in high-fat diet-induced obesity and MAFLD in mice.Life science alliance · 2025Article
- Unveiling the hidden dangers: a review of non-apoptotic programmed cell death in anesthetic-induced developmental neurotoxicity.Cell biology and toxicology · 2024Review
- The regulated cell death at the maternal-fetal interface: beneficial or detrimental?Cell death discovery · 2024Review
- Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.Cell death & disease · 2024Article
- An intracellular bacterial pathogen triggers RIG-I/MDA5-dependent necroptosis.Current research in microbial sciences · 2024Article
- Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.Nature communications · 2023Article
- A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.Nature communications · 2023Article
- The VEGFR/PDGFR tyrosine kinase inhibitor, ABT-869, blocks necroptosis by targeting RIPK1 kinase.The Biochemical journal · 2023Article
- Role of necroptosis in kidney health and disease.Nature reviews. Nephrology · 2023Review
- Pore-forming proteins as drivers of membrane permeabilization in cell death pathways.Nature reviews. Molecular cell biology · 2023Review
- From (Tool)Bench to Bedside: The Potential of Necroptosis Inhibitors.Journal of medicinal chemistry · 2023Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Necroptosis is a lytic programmed cell death pathway with origins in innate immunity that is frequently dysregulated in inflammatory diseases. The terminal effector of the pathway, MLKL, is licensed to kill following phosphorylation of its pseudokinase domain by the upstream regulator, RIPK3 kinase. Phosphorylation provokes the unleashing of MLKL's N-terminal four-helix bundle (4HB or HeLo) domain, which binds and permeabilizes the plasma membrane to cause cell death. The precise mechanism by which the 4HB domain permeabilizes membranes, and how the mechanism differs between species, remains unclear. Here, we identify the membrane binding epitope of mouse MLKL using NMR spectroscopy. Using liposome permeabilization and cell death assays, we validate K69 in the α3 helix, W108 in the α4 helix, and R137/Q138 in the first brace helix as crucial residues for necroptotic signaling. This epitope differs from the phospholipid binding site reported for human MLKL, which comprises basic residues primarily located in the α1 and α2 helices. In further contrast to human and plant MLKL orthologs, in which the α3-α4 loop forms a helix, this loop is unstructured in mouse MLKL in solution. Together, these findings illustrate the versatility of the 4HB domain fold, whose lytic function can be mediated by distinct epitopes in different orthologs.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.