Journal
MOLECULAR CELL
Volume 59, Issue 1, Pages 35-49Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.04.026
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Funding
- New Scholar awards from Sidney Kimmel Foundation for Cancer Research
- Ellison Medical Foundation
- Hellman Fellowship
- San Diego Center for Systems Biology
- UCSD Cell and Molecular Genetics Training Program [T32 GM007240]
- [NIH 5R01GM092748-04]
- [NIH RO1 GM05054516]
- MRC [MR/L001209/1] Funding Source: UKRI
- Medical Research Council [1369974, MR/L001209/1] Funding Source: researchfish
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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 eIF2 alpha 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.
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