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Updated: Oct 18, 2025

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

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MLKL and CaMKII Are Involved in RIPK3-Mediated Smooth Muscle Cell Necroptosis

Ting Zhou1, Elise DeRoo1, Huan Yang1

  • 1Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.

Cells
|September 28, 2021
PubMed

Insights

Receptor interacting protein kinase 3 (RIPK3) triggers smooth muscle cell (SMC) necroptosis in abdominal aortic aneurysms (AAAs). This study reveals mixed lineage kinase domain-like pseudokinase (MLKL) acts upstream of calcium/calmodulin-dependent protein kinase II (CaMKII) in this RIPK3-mediated process.

Area of Science:

  • Cardiovascular Biology
  • Cell Death Pathways
  • Molecular Signaling

Background:

  • Receptor interacting protein kinase 3 (RIPK3)-mediated necroptosis in smooth muscle cells (SMCs) contributes to abdominal aortic aneurysm (AAA) pathogenesis.
  • The precise downstream signaling cascade of RIPK3 in SMC necroptosis remains largely unelucidated.

Purpose of the Study:

  • To investigate the roles of mixed lineage kinase domain-like pseudokinase (MLKL) and calcium/calmodulin-dependent protein kinase II (CaMKII) in RIPK3-dependent SMC necroptosis.
  • To determine the sequential order of MLKL and CaMKII activation in this pathway.

Main Methods:

  • Utilized a murine CaCl2-induced abdominal aortic aneurysm model.
  • Employed in vitro TNFα plus zVAD-FMK stimulation of mouse aortic SMCs to induce necroptosis.
  • Investigated the effects of MLKL and CaMKII inhibition/silencing on cell death and signaling events using siRNA and specific inhibitors.

Main Results:

  • Both MLKL and CaMKII were phosphorylated in SMCs during AAA development and in vitro necroptosis induction.
  • RIPK3 deficiency attenuated MLKL and CaMKII phosphorylation.
  • MLKL knockdown reduced SMC necroptosis and CaMKII phosphorylation, while CaMKII inhibition/silencing partially inhibited necroptosis without affecting MLKL.
  • MLKL activation appears to precede CaMKII activation in the RIPK3-mediated necroptosis pathway.

Conclusions:

  • MLKL and CaMKII are both critical effectors in RIPK3-mediated SMC necroptosis.
  • MLKL functions upstream of CaMKII in the signaling pathway leading to SMC death in AAA pathogenesis.
Keywords:
CaMKIIMLKLabdominal aortic aneurysmnecroptosissmooth muscle cells

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