title: Overexpression of CHOP in Myelinating Cells Does Not Confer a Significant Phenotype under Normal or Metabolic Stress Conditions.
abstract: The PKR-like endoplasmic reticulum kinase (PERK) pathway of the unfolded protein response (UPR) is protective against toxic accumulations of misfolded proteins in the endoplasmic reticulum, but is thought to drive cell death via the transcription factor, CHOP. However, in many cell types, CHOP is an obligate step in the PERK pathway, which frames the conundrum of a prosurvival pathway that kills cells. Our laboratory and others have previously demonstrated the prosurvival activity of the PERK pathway in oligodendrocytes. In the current study, we constitutively overexpress CHOP in myelinating cells during development and into adulthood under normal or UPR conditions. We show that this transcription factor does not drive apoptosis. Indeed, we observe no detriment in mice at multiple levels from single cells to mouse behavior and life span. In light of these data and other studies, we reinterpret PERK pathway function in the context of a stochastic vulnerability model, which governs the likelihood that cells undergo cell death upon cessation of UPR protection and while attempting to restore homeostasis.
  
  
  
  Herein, we tackle the biggest controversy in the UPR literature: the function of the transcription factor CHOP as a protective or a prodeath factor. This manuscript is timely in light of the 2014 Lasker award for the UPR. Our in vivo data show that CHOP is not a prodeath protein, and we demonstrate that myelinating glial cells function normally in the presence of high CHOP expression from development to adulthood. Further, we propose a simplified view of UPR-mediated cell death after CHOP induction. We anticipate our work may turn the tide of the dogmatic view of CHOP and cause a reinvestigation of its function in different cell types. Accordingly, we believe our work will be a watershed for the UPR field.
authors.affiliation: Center for Molecular Medicine and Genetics.
authors.forename: Cherie M
authors.identifier: 0000-0002-4638-6899
authors.initials: CM
authors.lastname: Southwood
authors.affiliation: Center for Molecular Medicine and Genetics.
authors.forename: Bozena
authors.initials: B
authors.lastname: Fykkolodziej
authors.affiliation: Center for Molecular Medicine and Genetics.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Maheras
authors.affiliation: Carman and Ann Adams Department of Pediatrics.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Garshott
authors.affiliation: Center for Molecular Medicine and Genetics.
authors.forename: Molly
authors.initials: M
authors.lastname: Estill
authors.affiliation: Carman and Ann Adams Department of Pediatrics, Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fribley
authors.affiliation: Center for Molecular Medicine and Genetics, Carman and Ann Adams Department of Pediatrics, Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201 Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201 agow@med.wayne.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gow
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009900:Optic Nerve / Q000473:pathology; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology; D013312:Stress, Physiological / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
chemical_list: C497249:DDIT3 protein, human; D009419:Nerve Tissue Proteins; D051742:Transcription Factor CHOP; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse
keywords: Ddit3; GADD153; apoptosis; cell survival; homeostasis; metabolic stress