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Oligomerization in endoplasmic reticulum stress signaling
Saïd Taouji1, Sebastian Wolf, Eric Chevet
1Inserm U1053, Université Bordeaux Segalen, Bordeaux, France.
Summary
Protein complex oligomerization is key to endoplasmic reticulum (ER) function and the unfolded protein response (UPR). This study details how ER stress transducers, like inositol-requiring enzyme-1 (IRE1), oligomerize to regulate UPR signaling.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- Protein complex oligomerization is crucial for endoplasmic reticulum (ER) functions, including the unfolded protein response (UPR).
- The UPR is an adaptive cellular mechanism activated by misfolded protein accumulation in the ER.
- Transmembrane ER stress transducers, such as inositol-requiring enzyme-1 (IRE1) and protein kinase RNA-like ER kinase, play vital roles in UPR signaling.
Purpose of the Study:
- To review recent advances in understanding the oligomerization of ER stress transducers.
- To focus on the role of IRE1 oligomerization in UPR signaling.
- To describe the mechanisms by which oligomerization modulates UPR signal activation and deactivation.
Main Methods:
- Literature review of recent molecular characterization studies.
- Analysis of oligomerization-dependent mechanisms in ER stress signaling.
- Focus on IRE1 as a key ER stress transducer.
Main Results:
- Oligomerization of ER stress transducers like IRE1 is essential for initiating and propagating the UPR.
- IRE1 oligomerization activates UPR-specific transcription factors to restore ER homeostasis.
- Mechanisms governing the on/off switching of UPR signals through IRE1 oligomerization have been elucidated.
Conclusions:
- Oligomerization of ER stress transducers is a fundamental process for managing ER stress.
- Understanding IRE1 oligomerization provides insights into UPR regulation in health and disease.
- Targeting these oligomerization-dependent mechanisms could lead to novel therapeutic strategies for ER-related disorders.
Related Concept Videos
01:31Regulation 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...
01:37The Unfolded Protein Response
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...
01:17Role of ER in the Secretory Pathway
Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
01:32Export of Misfolded Proteins out of the ER
After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
01:29Protein Folding Quality Check in the RER
ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
01:26Protein Modifications in the RER
Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal sequences.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal sequences.