The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1

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Abstract

The protein folding capacity of the endoplasmic reticulum (ER) is tightly regulated by a network of signaling pathways, known as the unfolded protein response (UPR). UPR sensors monitor the ER folding status to adjust ER folding capacity according to need. To understand how the UPR sensor IRE1 maintains ER homeostasis, we identified zero-length crosslinks of RNA to IRE1 with single nucleotide precision in vivo. We found that IRE1 specifically crosslinks to a subset of ER-targeted mRNAs, SRP RNA, ribosomal and transfer RNAs. Crosslink sites cluster in a discrete region of the ribosome surface spanning from the A-site to the polypeptide exit tunnel. Moreover, IRE1 binds to purified 80S ribosomes with high affinity, indicating association with ER-bound ribosomes. Our results suggest that the ER protein translocation and targeting machineries work together with the UPR to tune the ER's protein folding load.

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All data analysed during this study are included in the manuscript and supporting files.

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Diego Acosta-Alvear

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

For correspondence
daa@lifesci.ucsb.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1139-8486
Gülsün Elif Karagöz

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

For correspondence
elif@walterlab.ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3392-2250
Florian Fröhlich

Harvard School of Public Health, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8307-2189
Han Li

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Tobias C Walther

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Peter Walter

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

For correspondence
peter@walterlab.ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

Funding

Howard Hughes Medical Institute (Investigator)

Peter Walter

Cancer Research Institute (Postdoctoral fellowship)

Diego Acosta-Alvear

Howard Hughes Medical Institute (Investigator)

Tobias C Walther

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.