Brain-derived neurotrophic factor suppresses tunicamycin-induced upregulation of CHOP in neurons.
The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers ER stress. ER stress initiates a number of specific compensatory signaling pathways including unfolded protein response (UPR). UPR is characterized by translational attenuation, synthesis of ER chaperone proteins such as glucose-regulated protein of 78 kDa (GRP78, also known as Bip), and transcriptional induction, which includes the activation of transcription factors such as activating transcriptional factor 6 (ATF6) and C/EBP homologous protein (CHOP, also known as growth arrest and DNA damage-inducible gene 153 [GADD153]). Sustained ER stress ultimately leads to cell death. ER functions are believed to be impaired in various neurodegenerative diseases, as well as in some acute disorders of the brain. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, functions as a neuroprotective agent and rescues neurons from various insults. The molecular mechanisms underlying BDNF neuroprotection, however, remain to be elucidated. We showed that CHOP partially mediated ER stress-induced neuronal death. BDNF suppressed ER stress-induced upregulation/ nuclear translocation of CHOP. The transcription of CHOP is regulated by ATF4, ATF6, and XBP1; BDNF selectively blocked the ATF6/CHOP pathway. Furthermore, BDNF inhibited the induction of death receptor 5 (DR5), a transcriptional target of CHOP. Our study thus suggests that suppression of CHOP activation may contribute to BDNF-mediated neuroprotection during ER stress responses.
Chen
Gang
G
Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, West Virginia 26506, USA.
Fan
Zhiqin
Z
Wang
Xin
X
Ma
Cuiling
C
Bower
Kimberly A
KA
Shi
Xianglin
X
Ke
Zun-Ji
ZJ
Luo
Jia
J
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D014415:Tunicamycin / Q000494:pharmacology*; D015854:Up-Regulation
D019208:Brain-Derived Neurotrophic Factor; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; C497251:Ddit3 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D014415:Tunicamycin; D051742:Transcription Factor CHOP