A feed-forward loop involving Trib3, Akt and FoxO mediates death of NGF-deprived neurons

Cell Death Differ. 2013 Dec;20(12):1719-30. doi: 10.1038/cdd.2013.128.

Abstract

The mechanisms governing neuron death following NGF deprivation are incompletely understood. Here, we show that Trib3, a protein induced by NGF withdrawal, has a key role in such death via a loop involving the survival kinase Akt and FoxO transcription factors. Trib3 overexpression is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn. Mechanism studies reveal that Trib3 interferes with phosphorylation/activity of Akt and contributes to Akt inactivation after NGF deprivation. FoxO1a, a direct Akt substrate, is dephosphorylated upon NGF withdrawal and consequently undergoes nuclear translocation and activates pro-apoptotic genes. We find that Trib3 is required for FoxO1a dephosphorylation and nuclear translocation after NGF deprivation. Conversely, Trib3 induction requires FoxO transcription factors, which show enhanced occupancy of the Trib3 promoter region following NGF withdrawal. Collectively, these findings support a mechanism in which NGF deprivation, Akt dephosphorylation/inactivation, FoxO dephosphorylation/activation and Trib3 induction are linked in a self-amplifying feed-forward loop that culminates in neuron death.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / metabolism
  • Cell Death / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Forkhead Transcription Factors / metabolism*
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Nerve Growth Factor / deficiency*
  • Nerve Growth Factor / pharmacology
  • Nerve Tissue Proteins
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / pathology*
  • PC12 Cells
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Small Interfering / metabolism
  • Rats
  • Repressor Proteins / metabolism
  • Substrate Specificity / drug effects

Substances

  • Cell Cycle Proteins
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • Repressor Proteins
  • TRIB3 protein, human
  • Trib3 protein, rat
  • Foxo1 protein, rat
  • Nerve Growth Factor
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • JNK Mitogen-Activated Protein Kinases