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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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ApoER2 processing by presenilin-1 modulates reelin expression.

Valeria Balmaceda1, Inmaculada Cuchillo-Ibáñez, Lluis Pujadas

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FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
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Summary
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Presenilin 1 (PS1) and gamma-secretase processing of the reelin receptor ApoER2 inhibit reelin expression. This suggests a novel regulatory mechanism for reelin signaling in the brain.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Reelin signaling is crucial for synaptic plasticity and neurotransmission.
  • The reelin pathway involves the receptor apolipoprotein E receptor 2 (ApoER2) and its cleavage by secretases.
  • Presenilin 1 (PS1) is the catalytic component of the gamma-secretase complex.

Purpose of the Study:

  • To investigate the role of PS1/gamma-secretase in ApoER2 processing and its effect on reelin expression.
  • To elucidate the regulatory mechanism of reelin signaling.

Main Methods:

  • Conditional-knockout mice lacking PS1.
  • Human SH-SY5Y neuroblastoma cell line.
  • Pharmacologic inhibition of gamma-secretase.
  • Luciferase reporter gene assay, nuclear fractionation, and chromatin immunoprecipitation.

Main Results:

  • PS1 deficiency increased brain ApoER2 and reelin levels.
  • ApoER2 processing by PS1/gamma-secretase produces an intracellular fragment.
  • This intracellular fragment suppresses reelin expression transcriptionally by binding to the RELN promoter.

Conclusions:

  • PS1/gamma-secretase-dependent processing of ApoER2 negatively regulates reelin expression.
  • This pathway represents a novel feedback mechanism controlling reelin signaling.