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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 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.

Original publication

DOI

10.1016/j.molcel.2015.04.026

Type

Journal article

Journal

Molecular cell

Publication Date

07/2015

Volume

59

Pages

35 - 49

Addresses

Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.

Keywords

Cell Line, Endoplasmic Reticulum, Animals, Humans, Drosophila, Saccharomyces cerevisiae, eIF-2 Kinase, Eukaryotic Initiation Factor-2, Cell Survival, Protein Biosynthesis, Gene Expression Regulation, Amino Acid Sequence, Phosphorylation, Molecular Sequence Data, Ribosome Subunits, Small, Eukaryotic, Ubiquitination, Unfolded Protein Response, Endoplasmic Reticulum Stress