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Regulation of the Unfolded Protein Response

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...

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Export of Misfolded Proteins out of the ER

Export 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...

Regulation of Nuclear Protein Sorting

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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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Related Experiment Video

Updated: Mar 9, 2026

Production of Nurr-1 Specific Polyclonal Antibodies Free of Cross-reactivity Against Its Close Homologs, Nor1 and Nur77

Production of Nurr-1 Specific Polyclonal Antibodies Free of Cross-reactivity Against Its Close Homologs, Nor1 and Nur77

Published on: August 17, 2015

New connections: NHERF gates activity.

Nancy R Gough¹

¹Science Signaling, AAAS, Washington, DC 20005, USA.

Science Signaling

|January 12, 2017

Summary

The study shows that NHERF proteins regulate TRPC4 and TRPC5 ion channels and ensure proper CFTR protein function. These molecular adaptors are key to controlling ion channel activity and protein quality control.

Area of Science:

Molecular biology
Cellular physiology
Ion channel research

Background:

NHERF proteins are crucial scaffolding molecules involved in various cellular processes.
TRPC4 and TRPC5 are calcium-permeable ion channels implicated in diverse physiological functions.
CFTR (Cystic Fibrosis Transmembrane conductance Regulator) is a chloride channel vital for epithelial cell function.

Purpose of the Study:

To elucidate the role of NHERF proteins in the regulation of TRPC4 and TRPC5 ion channels.
To investigate how NHERF proteins interact with and are recognized by the CFTR quality control checkpoint.

Main Methods:

Utilized molecular cloning and protein expression techniques.
Employed electrophysiological recordings to assess ion channel activity.

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Last Updated: Mar 9, 2026

Production of Nurr-1 Specific Polyclonal Antibodies Free of Cross-reactivity Against Its Close Homologs, Nor1 and Nur77

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Performed co-immunoprecipitation assays to study protein-protein interactions.

Main Results:

Demonstrated that NHERF proteins act as regulatory gates for diacylglycerol-mediated activation of TRPC4 and TRPC5 channels.
Showed that NHERF proteins are essential for the recognition of CFTR by the cellular quality control machinery.
Identified specific interaction domains between NHERF and both TRP channels and CFTR.

Conclusions:

NHERF proteins play a dual role as regulators of TRPC channel activity and facilitators of CFTR quality control.
These findings highlight the versatility of NHERF adaptors in integrating signaling pathways and maintaining cellular homeostasis.
Targeting NHERF interactions may offer therapeutic strategies for conditions involving TRPC channel dysfunction or CFTR defects.