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Updated: May 15, 2025

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
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MLKL activity requires a splicing-regulated, druggable intramolecular interaction.

Uris Ros1, Veronica Martinez-Osorio2, Pedro A Valiente3

  • 1Institute of Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany; Max Planck Institute of Biophysics, Frankfurt am Main 60439, Germany.

Molecular Cell
|April 10, 2025
PubMed
Summary

Alternative splicing of microexons in mixed lineage kinase domain-like (MLKL) controls necroptosis. This discovery identifies a new strategy for developing MLKL inhibitors to treat inflammatory diseases.

Keywords:
MLKLabdominal aortic aneurysmdrug discoveryinflammatory diseasesmembrane permeabilizationmicroexonsnecroptosisskin inflammationsmall molecule inhibitorssplicing variants

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Area of Science:

  • Molecular Biology
  • Cell Death Research
  • Immunology

Background:

  • Necroptosis is an inflammatory cell death pathway implicated in various human diseases.
  • The pseudokinase mixed lineage kinase domain-like (MLKL) protein is crucial for executing necroptosis.
  • The precise mechanisms regulating MLKL activity remain incompletely understood.

Purpose of the Study:

  • To investigate the role of alternative splicing in MLKL function.
  • To identify novel therapeutic targets for necroptosis-driven pathologies.
  • To explore the structural basis of MLKL activation.

Main Methods:

  • Analysis of MLKL splicing variants and their impact on cell death.
  • Structural studies to identify MLKL interaction sites.
  • Development and testing of small molecule inhibitors targeting MLKL.
  • In vivo studies using murine models of inflammatory diseases.

Main Results:

  • A splicing-dependent insertion in MLKL's C-terminal helix creates an anti-necroptotic isoform.
  • Interaction with a novel hydrophobic groove on MLKL is essential for necroptosis.
  • Small molecules inhibiting MLKL ameliorated disease in mouse models of dermatitis and aortic aneurysm.
  • Alternative splicing regulates MLKL's intramolecular rearrangement critical for necroptosis.

Conclusions:

  • Alternative splicing of microexons provides a regulatory mechanism for MLKL-mediated necroptosis.
  • Targeting the MLKL hydrophobic groove offers a promising strategy for developing allosteric inhibitors.
  • This research paves the way for new treatments for diseases involving necroptosis.