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Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

11.3K

Pannexin-1 limits the production of proinflammatory cytokines during necroptosis

Tiphaine Douanne1,2,3, Gwennan André-Grégoire1,2,3,4, Kilian Trillet1,2,3

  • 1CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France.

EMBO Reports
|August 15, 2019
PubMed

Insights

Mixed lineage kinase-like (MLKL) activation during necroptosis controls cell death. MLKL oligomers activate Pannexin-1 (PANX1) channels, requiring RAB27 GTPases, and influence inflammation.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Receptor-interacting protein kinase-3 (RIPK3) activates mixed lineage kinase-like (MLKL) to control necroptosis.
  • Active MLKL oligomers disrupt plasma membrane integrity and regulate extracellular vesicle biogenesis and cytokine production.
  • The precise molecular mechanisms governing these early necroptosis events are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which MLKL oligomers influence cellular events during necroptosis.
  • To investigate the role of Pannexin-1 (PANX1) channels and RAB GTPases in MLKL-mediated necroptosis.
  • To identify novel signaling pathways linking MLKL to inflammation during necroptosis.

Main Methods:

  • Cell-based assays to study necroptosis.
  • Silencing and inhibition of PANX1 channels.
  • Analysis of RAB GTPase involvement in MLKL-mediated membrane events.
  • Cytokine production measurements (e.g., interleukin-8).

Main Results:

  • MLKL oligomers were found to activate PANX1 channels, coinciding with the loss of phosphatidylserine asymmetry.
  • Activation of PANX1 channels by MLKL oligomers requires RAB27A and RAB27B small GTPases.
  • While PANX1 silencing or inhibition did not prevent necroptotic cell death, it led to increased production of proinflammatory cytokines like interleukin-8.

Conclusions:

  • A novel signaling nexus involving MLKL, RAB27 GTPases, and PANX1 channels in necroptosis has been identified.
  • PANX1 activation by MLKL may modulate the inflammatory response during necroptosis.
  • These findings offer potential targets for interfering with necroptosis-associated inflammation.
Keywords:
MLKLPannexin-1cytokinesinflammationnecroptosis

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