Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe
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 geneti...
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Format: | Article |
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eLife Sciences Publications Ltd
2017-09-01
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Series: | eLife |
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Online Access: | https://elifesciences.org/articles/29216 |
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author | Nicholas R Guydosh Philipp Kimmig Peter Walter Rachel Green |
author_facet | Nicholas R Guydosh Philipp Kimmig Peter Walter Rachel Green |
author_sort | Nicholas R Guydosh |
collection | DOAJ |
description | 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. |
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id | doaj.art-e2311e0be31d43d19f18dadee113fec8 |
institution | Directory Open Access Journal |
issn | 2050-084X |
language | English |
last_indexed | 2024-04-12T12:15:06Z |
publishDate | 2017-09-01 |
publisher | eLife Sciences Publications Ltd |
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series | eLife |
spelling | doaj.art-e2311e0be31d43d19f18dadee113fec82022-12-22T03:33:27ZengeLife Sciences Publications LtdeLife2050-084X2017-09-01610.7554/eLife.29216Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombeNicholas R Guydosh0Philipp Kimmig1Peter Walter2https://orcid.org/0000-0002-6849-708XRachel Green3https://orcid.org/0000-0001-9337-2003Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States; Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, United StatesDepartment of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States; Institute of Biochemistry, ETH Zurich, Zurich, SwitzerlandDepartment of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United StatesThe 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.https://elifesciences.org/articles/29216proteostasisRNA decayribosome stallingendonucleaseribosome footprintingribosome quality control |
spellingShingle | Nicholas R Guydosh Philipp Kimmig Peter Walter Rachel Green Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe eLife proteostasis RNA decay ribosome stalling endonuclease ribosome footprinting ribosome quality control |
title | Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe |
title_full | Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe |
title_fullStr | Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe |
title_full_unstemmed | Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe |
title_short | Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe |
title_sort | regulated ire1 dependent mrna decay requires no go mrna degradation to maintain endoplasmic reticulum homeostasis in s pombe |
topic | proteostasis RNA decay ribosome stalling endonuclease ribosome footprinting ribosome quality control |
url | https://elifesciences.org/articles/29216 |
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