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15.16: Regulation of the Unfolded Protein Response
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Cell Biology

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Regulation of the Unfolded Protein Response
 
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15.16: Regulation of the Unfolded Protein Response

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 activates its kinase domain, which then trans-autophosphorylates each other, exposing the endoribonuclease or RNA-splicing domains.

IRE1 and ER Stress Regulation

Activated IRE1 molecules form a multimeric assembly that unconventionally carries out spliceosome-independent splicing of the mRNA encoding X-box binding protein one, or XBP1. XBP1 is a transcription activator that upregulates the production of proteins required for ER folding and degradation. Besides XBP1 mRNA, IRE1 cleaves other mRNA substrates by the regulated IRE1-dependent decay of messenger RNAs or RIDD. The target mRNAs for RIDD carry a consensus sequence in their cleavage sites, which helps form a stem-loop structure for recognition by IRE1. RIDD reduces the number of nascent proteins directed to the ER lumen or membrane and reduces the load on protein folding and quality check in the ER.

During proteotoxic stress, the IRE1 response can activate UPR to help establish protein homeostasis in the ER. If the UPR fails to salvage the cell by reducing the ER protein overload, IRE1 initiates cell death through the decay of anti-apoptotic microRNAs. Thus, IRE1 signaling is involved in fundamental cellular physiology and homeostasis.


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