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Mol Cell. 2015 Jul 2;59(1):35-49. doi: 10.1016/j.molcel.2015.04.026. Epub 2015 Jun 4.

The Unfolded Protein Response Triggers Site-Specific Regulatory Ubiquitylation of 40S Ribosomal Proteins.

Author information

1
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
2
Cancer Structural Biology, Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
3
Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford OX3 7DQ, United Kingdom.
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Contributed equally

Abstract

Insults to ER homeostasis activate the unfolded protein response (UPR), which elevates protein folding and degradation capacity and attenuates protein synthesis. While a role for ubiquitin in regulating the degradation of misfolded ER-resident proteins is well described, ubiquitin-dependent regulation of translational reprogramming during the UPR remains uncharacterized. Using global quantitative ubiquitin proteomics, we identify evolutionarily conserved, site-specific regulatory ubiquitylation of 40S ribosomal proteins. We demonstrate that these events occur on assembled cytoplasmic ribosomes and are stimulated by both UPR activation and translation inhibition. We further show that ER stress-stimulated regulatory 40S ribosomal ubiquitylation occurs on a timescale similar to eIF2α phosphorylation, is dependent upon PERK signaling, and is required for optimal cell survival during chronic UPR activation. In total, these results reveal regulatory 40S ribosomal ubiquitylation as an important facet of eukaryotic translational control.

PMID:
26051182
PMCID:
PMC4491043
DOI:
10.1016/j.molcel.2015.04.026
[Indexed for MEDLINE]
Free PMC Article

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