Mammalian IRE1α dynamically and functionally coalesces with stress granules

Area of Science:

• Cellular Biology
• Molecular Biology
• Biochemistry

Background:

• Endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR).
• Inositol-requiring enzyme 1 (IRE1) is a key sensor and effector in the UPR pathway.
• Activated IRE1 forms clusters, but their structure and function are poorly understood.

Purpose of the Study:

• To investigate the dynamic architecture and functional properties of IRE1 clusters during ER stress.
• To elucidate the mechanism underlying IRE1 cluster formation and its relationship with stress granules (SGs).
• To understand how IRE1 clustering impacts the efficiency of the IRE1-XBP1 pathway.

Main Methods:

• Utilized mammalian cell models to study IRE1α clustering dynamics.
• Investigated the role of intrinsically disordered regions in IRE1α's cytosolic linker.
• Assessed the impact of disrupting SG assembly on IRE1α clustering and XBP1 splicing.

Main Results:

• IRE1α cluster formation is an ER membrane-bound phase separation event coupled to SG assembly.
• IRE1α clusters are dynamically tethered to SGs at the ER in response to various stressors.
• Disruption of SG assembly abrogated IRE1α clustering and impaired XBP1 mRNA splicing.
• IRE1α-SG coalescence enriched pro-survival pathway components, enhancing stress handling capacity.

Conclusions:

• IRE1α clustering represents a phase transition mechanism involving SG coalescence.
• This spatiotemporal assembly of IRE1α-SG condensates optimizes IRE1α machinery function.
• The findings reveal a novel mechanism for enhanced cellular stress resilience via the IRE1-XBP1 pathway.