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Updated: Jul 17, 2025
08:55
Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
Published on: August 7, 2018
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Acylation of MLKL impacts its function in necroptosis
Apoorva J Pradhan1, Shweta Chitkara1, Ricardo X Ramirez2
1Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.
Biorxiv : the Preprint Server for Biology
|August 30, 2023
Summary
S-acylation of mixed lineage kinase domain-like (MLKL) protein regulates necroptosis. Blocking this modification destabilizes MLKL, reducing cell death and inflammation.
Area of Science:
- Cellular signaling pathways
- Molecular mechanisms of cell death
- Protein post-translational modifications
Background:
- Mixed lineage kinase domain-like (MLKL) is central to necroptosis, a regulated form of cell death.
- Activated MLKL (pMLKL) permeabilizes cell membranes, driving inflammation.
- Previous work indicated MLKL and pMLKL undergo S-acylation during necroptosis.
Approach:
- Characterized MLKL S-acylation sites, identifying C184, C269, and C286 as potential sites.
- Employed all-atom molecular dynamics simulations to study acylation's impact on MLKL-membrane interactions.
- Investigated S-palmitoyltransferases, pinpointing zDHHC21 as crucial for pMLKL acylation.
Key Points:
- MLKL acylation occurs at specific cysteine residues.
- Acylation alters MLKL's interaction with cell membranes.
- zDHHC21 activity is essential for pMLKL acylation and subsequent membrane localization.
Conclusions:
- Inhibiting pMLKL acylation destabilizes the protein, leading to its degradation and reduced necroptosis.
- S-acylation critically influences MLKL function and membrane association in necroptosis.
- Targeting MLKL acylation offers a potential therapeutic strategy to ameliorate necroptotic activity.
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