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Regulation of the Unfolded Protein Response
The accumulation of misfolded proteins in the ER lumen results in ER stress.
The N-terminal domain of IRE1 protein senses the ER stress and gets activated to initiate the unfolded protein response or UPR.
The activated IRE1 molecules form homodimers and use their cytosolic kinase domains to phosphorylate each other.
The dimerized IRE1 molecules club together in a rod-shaped complex forming a surface with endoribonuclease activity.
This surface splices out an intron from the pre-mRNA encoding a transcription factor, X-box binding protein one or XBP1.
The mature mRNA translates into XBP1 protein, which is imported into the nucleus.
Inside the nucleus, XBP1 binds ER response elements on the DNA, activating the transcription of UPR target genes, like chaperones.
Next, the chaperone encoding mRNAs are exported out of the nucleus and bound by ribosomes.
The ribosomes carry the mRNAs to the ER membrane for cotranslational translocation.
As a result, there is an increased influx of chaperone molecules in the ER lumen.
These chaperones correctly refold misfolded proteins so that they can be cleared from the ER.
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.
Suggested Reading
- Coelho, Dina S., and Pedro M. Domingos. "Physiological roles of regulated Ire1 dependent decay." Frontiers in genetics 5 (2014): 76.
- Adams, Christopher J., Megan C. Kopp, Natacha Larburu, Piotr R. Nowak, and Maruf MU Ali. "Structure and molecular mechanism of ER stress signaling by the unfolded protein response signal activator IRE1." Frontiers in Molecular Biosciences 6 (2019): 11.