AUTHOR=Liu Jin , Amar Fatou , Corona Carlo , So Raphaella W. L. , Andrews Stuart J. , Nagy Peter L. , Shelanski Michael L. , Greene Lloyd A. 

TITLE=Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4) in Neurons and Promotes ATF4-Dependent Induction of Sesn2

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=Volume 11 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2018.00062

DOI=10.3389/fnmol.2018.00062

ISSN=1662-5099

ABSTRACT=Activating Transcription Factor 4 (ATF4) plays important physiologic roles in the brain including regulation of learning and memory as well as neuronal survival and death. Yet, outside of translational regulation by the eIF2-dependent stress response pathway, there is little information about how its levels are controlled in neurons.  Here, we show that brain-derived neurotrophic factor (BDNF) promotes a rapid and sustained increase in neuronal ATF4 transcripts and protein levels. This increase is dependent on TrkB signaling, but independent of levels of phosphorylated eIF2.  The elevation in ATF4 protein occurs both in nuclei and processes.  Transcriptome analysis revealed that ATF4 mediates BDNF-promoted induction of Sesn2 which encodes Sestrin2, a protector against oxidative and genotoxic stresses and a mTor complex 1 inhibitor.  In contrast, BDNF-elevated ATF4 did not affect expression of a number of other known ATF4 targets including several with pro-apoptotic activity.  The capacity of BDNF to elevate neuronal ATF4 may thus represent a means to maintain this transcription factor at levels that provide neuroprotection and optimal brain function without risk of triggering neurodegeneration.