Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe

Abstract
Data availability
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Abstract

The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.

Data availability

The following data sets were generated

1. Guydosh NR
2. Kimmig P
3. Green R
4. Walter P
(2017) Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE98934).

https://https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE98934

The following previously published data sets were used

1. Kimmig P
2. Diaz M
3. Lang A
4. Zheng J
5. Williams C
6. Aragón T
7. Li H
8. Walter P
(2012) The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE40298).

https://cdn.elifesciences.org/articles/29216/https:/https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE40298

Article and author information

Author details

Nicholas R Guydosh

Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States

Competing interests
No competing interests declared.
Phillip Kimmig

Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
No competing interests declared.
Peter Walter

Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

For correspondence
peter@walterlab.ucsf.edu

Competing interests
No competing interests declared.

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

Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States

For correspondence
ragreen@jhmi.edu

Competing interests
Rachel Green, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-9337-2003

Funding

Howard Hughes Medical Institute

Peter Walter
Rachel Green

National Institute of General Medical Sciences (GM 059425)

Rachel Green

National Institutes of Health

Peter Walter

National Institute of Diabetes and Digestive and Kidney Diseases

Nicholas R Guydosh

Human Frontier Science Program

Phillip Kimmig

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

Copyright

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.