IRE1α undergoes a dynamic filament assembly cycle governed by unfolded proteins and BiP.
- 1University of California, San Francisco
Abstract
The endoplasmic reticulum is a major hub of protein synthesis, modification and trafficking that relies on the Unfolded Protein Response (UPR) to balance its folding capacity. IRE1, the most conserved of the UPR sensors, undergoes a change in oligomeric state upon activation that propagates the stress signal from the ER lumen to its cytoplasmic kinase/RNase domains. Here we show that opposing inputs from unfolded proteins and the ER chaperone machinery govern a dynamic cycle of IRE1 assembly. A bona fide unfolded ER client directly binds the IRE1 lumenal domain (LD) and promotes higher-order oligomerization. Model peptides further reveal that full assembly into LD filaments depends on ligand length, sequence, and the IRE1 oligomerization interfaces. The ER Hsp70, BiP, counterbalances this process through two distinct mechanisms: i) an ATP-independent interaction via the BiP nucleotide-binding domain buffers early IRE1 assembly by engaging its oligomerization interface, whereas ii) ATP-regulated BiP/ERDJ machinery actively dismantles assembled filaments. Together, our findings reconcile direct unfolded protein recognition with BiP-mediated regulation to establish LD oligomerization as a point of integration through which unfolded protein load and chaperone availability dynamically regulate IRE1 assembly state and signalling.
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BibTeX
@misc{mendezmoran2026ire1α,
title = {{IRE1α undergoes a dynamic filament assembly cycle governed by unfolded proteins and BiP.}},
author = {M. Mendez-Moran and M. Le-Vasseur and D. N. Itzhak and W. Sadowska and G. E. Karagöz and P. Walter and D. A. Agard},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.760176},
url = {https://www.biorxiv.org/content/10.64898/2026.10.19.760176v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - IRE1α undergoes a dynamic filament assembly cycle governed by unfolded proteins and BiP.
AU - M. Mendez-Moran
AU - M. Le-Vasseur
AU - D. N. Itzhak
AU - W. Sadowska
AU - G. E. Karagöz
AU - P. Walter
AU - D. A. Agard
PY - 2026
DA - 2026/10/19
PB - bioRxiv
DO - 10.64898/2026.10.19.760176
UR - https://www.biorxiv.org/content/10.64898/2026.10.19.760176v1
AB - The endoplasmic reticulum is a major hub of protein synthesis, modification and trafficking that relies on the Unfolded Protein Response (UPR) to balance its folding capacity. IRE1, the most conserved of the UPR sensors, undergoes a change in oligomeric state upon activation that propagates the stress signal from the ER lumen to its cytoplasmic kinase/RNase domains. Here we show that opposing inputs from unfolded proteins and the ER chaperone machinery govern a dynamic cycle of IRE1 assembly. A bona fide unfolded ER client directly binds the IRE1 lumenal domain (LD) and promotes higher-order oligomerization. Model peptides further reveal that full assembly into LD filaments depends on ligand length, sequence, and the IRE1 oligomerization interfaces. The ER Hsp70, BiP, counterbalances this process through two distinct mechanisms: i) an ATP-independent interaction via the BiP nucleotide-binding domain buffers early IRE1 assembly by engaging its oligomerization interface, whereas ii) ATP-regulated BiP/ERDJ machinery actively dismantles assembled filaments. Together, our findings reconcile direct unfolded protein recognition with BiP-mediated regulation to establish LD oligomerization as a point of integration through which unfolded protein load and chaperone availability dynamically regulate IRE1 assembly state and signalling.
ER -