ER Stress Signaling in the CNS

Hypoxic-ischemic stress in the CNS is a potent stimulus for both gene expression and activation of the unfolded protein response originating from the endoplasmic reticulum (ER). Signals originating from receptors embedded within the ER influence protein-protein interactions between the family of bZIP transcription factors including C/EBP-beta, ATF4, and CHOP-10. It has been long recognized that the effects of ER signaling on both transcription and translation can control the balance between adaptive to pathologic transcription. However, the discrete signals that govern which of these influences dominate remain to be established.

We have found that the bZIP heterodimeric factors CHOP-10 and C/EBPb control both the development and post-ischemic survival of neurons. Ischemia-induced C/EBPb turnover predicts neuron loss and enforced expression is both neuroprotective pro-neuritogenic. These effects were dependent on the phosphatase DUSP1 that inhibits ERK-dependent phosphorylation of C/EBPb. We have also found that despite its established role in ER-dependent apoptotic signaling, CHOP-10 can convey neuroprotection. We are currently defining the post-translational modifications involved in CHOP’s divergent behavior and have evidence linking C/EBPb-CHOP-10 interactions in adaptive plasticity in both developmental and injury models.

  1. Halterman MW, Dejesus C, Rempe D, Schor NF and HJ Federoff. (2008) Loss of c/EBPb activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons.  Mol. Cell Neur. 38(2):125-37.  PMC2652244
  2. Halterman MW, Gill, M, Dejesus C, Giuliano R, Ogihara M, Schor NF and HJ Federoff.  (2010) The endoplasmic reticulum stress response factor, CHOP-10, protects against hypoxia induced neuronal death.  J. Biol. Chem.  285(28):21329-40. PMC2898390
  3. Rininger A, Dejesus C, Totten A, Wayland A, and MW Halterman.  (2012) MKP1 antagonizes C/EBPb activity and lowers the apoptotic threshold in models of CNS ischemia. Cell Death & Differentiation. PMC3438493