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DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression

Rupak Mukhopadhyay1, Partho Sarothi Ray, Abul Arif

  • 1Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Molecular Cell
|November 11, 2008
PubMed

Insights

Interferon-gamma triggers a kinase cascade that phosphorylates ribosomal protein L13a, inhibiting inflammatory gene translation. This pathway also represses the kinases themselves, forming a regulatory module for inflammation resolution.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • The interferon-gamma-activated inhibitor of translation (GAIT) complex represses inflammatory gene expression.
  • Phosphorylation of ribosomal protein L13a is critical for GAIT complex function.

Purpose of the Study:

  • To elucidate the kinase cascade regulating L13a phosphorylation and GAIT complex activity.
  • To investigate the role of this pathway in controlling inflammatory gene expression and resolution.

Main Methods:

  • Kinase assays to identify upstream activators of DAPK and ZIPK.
  • Analysis of L13a phosphorylation and ribosomal association.
  • mRNA and protein expression analysis of GAIT target genes.

Main Results:

  • IFN-gamma activates DAPK, which in turn activates ZIPK, leading to L13a phosphorylation at Ser(77).
  • Phosphorylated L13a is released from the ribosome, silencing translation of GAIT element-bearing mRNAs.
  • The mRNAs encoding DAPK and ZIPK are also targets of this inhibitory pathway.
  • Inhibition of DAPK and ZIPK allows for the re-induction of inflammatory gene expression.

Conclusions:

  • The DAPK-ZIPK-L13a axis is a novel regulatory module controlling inflammatory gene expression.
  • This pathway acts as a checkpoint in macrophage resolution of inflammation.
  • Defects in this axis may contribute to chronic inflammatory diseases.

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