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Cellular reactive oxygen species inhibit MPYS induction of IFNβ

Lei Jin1, Laurel L Lenz, John C Cambier

  • 1Integrated Department of Immunology, University of Colorado Denver School of Medicine and National Jewish Health, Denver, Colorado, United States of America.

Plos One
|December 21, 2010
PubMed

Insights

Reactive Oxygen Species (ROS) are detected by MPYS, also known as STING, which regulates Interferon-beta (IFNβ) expression. ROS form disulfide bonds in MPYS, inhibiting its activity and revealing a new regulatory mechanism.

Area of Science:

  • Immunology
  • Cellular Biology
  • Biochemistry

Background:

  • Inflammatory diseases and infections elevate cellular Reactive Oxygen Species (ROS).
  • MPYS (also known as STING) mediates Interferon-beta (IFNβ) expression during infection.
  • ROS are implicated in cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of MPYS as a sensor for Reactive Oxygen Species (ROS).
  • To elucidate the mechanism by which ROS regulate MPYS activity and IFNβ stimulation.

Main Methods:

  • Cellular assays to measure IFNβ expression and IRF3 activation.
  • Biochemical analysis to detect disulfide bond formation in MPYS.
  • Site-directed mutagenesis to identify key cysteine residues and redox motifs in MPYS.

Main Results:

  • MPYS functions as a direct sensor for cellular ROS.
  • ROS induce intermolecular disulfide bonds in MPYS homodimers, inhibiting its ability to stimulate IFNβ.
  • Specific cysteine residues (Cys-64, -148, -292, -309) and a Cys88xxCys91 redox motif are critical for MPYS function.

Conclusions:

  • MPYS is a novel ROS sensor that regulates the innate immune response.
  • ROS-mediated inhibition of MPYS activity provides a new mechanism for controlling IFNβ production.
  • Understanding this pathway has implications for inflammatory diseases and infections.

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