Original Paper

Cell Death and Differentiation (2013) 20, 1719–1730; doi:10.1038/cdd.2013.128

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

N Zareen1, S C Biswas2 and L A Greene1

  1. 1Department of Pathology and Cell Biology, Columbia University Medical Center, NY 10032, USA
  2. 2Cell Biology and Physiology division, CSIR-Indian Institute of Chemical Biology, Kolkata 700032, India

Correspondence: N Zareen, Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, P and S 15-401, New York, NY 10032, USA. Tel: +1212-305-6370; Fax: +1212 305 5498; E-mail: nz2131@caa.columbia.edu

Received 15 November 2012; Revised 30 July 2012; Accepted 1 August 2013

Edited by M Deshmuck

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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is sufficient to induce neuron death, and silencing of endogenous Trib3 strongly protects from death when NGF is withdrawn.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.

Keywords:

NGF; apoptosis; Akt; Trib3; FoxO

Abbreviations:

NGF, nerve growth factor; Ser, serine; Thr, threonine; Trk, tropomyosin receptor kinase; PI3K, phosphoinositide-3 kinase; FoxO, forkhead box, class O; ER, endoplasmic reticulum; JNK, Jun N-terminal kinase; ChIP, chromatin immunoprecipitation; SCG, superior cervical ganglion