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Electrophoretic Mobility Shift Assay (EMSA) for the Study of RNA-Protein Interactions: The IRE/IRP Example

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Published on: December 3, 2014

Principles of IRE1 modulation using chemical tools.

Kenneth P K Lee¹, Frank Sicheri

¹Program in Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

Methods in Enzymology

|January 27, 2011

Summary

Endoplasmic reticulum (ER) stress triggers the unfolded protein response (UPR). IRE1, a key sensor, activates transcription factor XBP1 (or HAC1) to resolve ER stress, with recent advances clarifying its mechanism.

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Area of Science:

Molecular Biology
Cellular Biology
Biochemistry

Background:

Endoplasmic reticulum (ER) stress arises from misfolded proteins, disrupting cellular homeostasis.
The unfolded protein response (UPR) is a critical cellular defense mechanism against ER stress.
IRE1 is a highly conserved ER transmembrane sensor crucial for initiating the UPR.

Purpose of the Study:

To review recent structural and molecular advances in understanding IRE1-mediated UPR signaling.
To highlight the mechanism of IRE1's activation of transcription factors XBP1/HAC1.
To propose principles for chemical modulation of IRE1 for therapeutic development.

Main Methods:

Structural biology (X-ray crystallography, cryo-EM).
Molecular biology techniques (mRNA cleavage assays, genetic manipulation).
Chemical biology approaches (small molecule screening, inhibitor design).

Main Results:

Recent studies have elucidated the structural basis of IRE1 activation and its nuclease function.
The mechanism of IRE1-mediated splicing of XBP1/HAC1 mRNA has been detailed.
Insights into IRE1's role in sensing and responding to ER stress have been significantly advanced.

Conclusions:

IRE1's ancient role in the UPR is critical for cellular survival under ER stress.
Structural and chemical biology provide powerful tools to probe IRE1 function.
Targeting IRE1 offers potential therapeutic strategies for diseases associated with ER stress.