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GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis

Nataly Shulga1, John G Pastorino

  • 1Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084, USA.

Journal of Cell Science
|March 7, 2012
PubMed

Insights

Tumor necrosis factor (TNF) triggers necroptosis, a programmed cell death pathway. This study reveals STAT3

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death
  • Signal transduction pathways

Background:

  • Tumor necrosis factor (TNF) induces necroptosis, a form of programmed necrosis.
  • Receptor-interacting serine/threonine-protein kinase 1 (RIPK-1) activity is crucial for necroptosis.
  • Mitochondrial reactive oxygen species (ROS) generation is essential for TNF-induced necroptosis.

Purpose of the Study:

  • To identify signaling components linking RIPK-1 to mitochondrial ROS production in TNF-induced necroptosis.
  • To elucidate the role of STAT3 in the necroptosis pathway.

Main Methods:

  • Investigated STAT3 phosphorylation at serine 727 during TNF-induced necroptosis.
  • Examined the interaction between phosphorylated STAT3 and GRIM-19, a mitochondrial complex I subunit.
  • Assessed the impact of STAT3 translocation on mitochondrial ROS production and cell death.

Main Results:

  • STAT3 phosphorylation at serine 727 is dependent on RIPK-1 activity.
  • Phosphorylated STAT3 interacts with GRIM-19, a subunit of mitochondrial complex I.
  • STAT3 translocation to mitochondria increases ROS production, leading to cell death.

Conclusions:

  • STAT3 acts as a critical mediator between RIPK-1 and mitochondrial dysfunction in TNF-induced necroptosis.
  • The RIPK-1-STAT3-GRIM-19 axis is a key pathway regulating necroptosis.
  • Targeting this pathway could offer therapeutic strategies for diseases involving necroptosis.

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