title: The Unfolded Protein Response Triggers Site-Specific Regulatory Ubiquitylation of 40S Ribosomal Proteins.
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.
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Reneé
authors.initials: R
authors.lastname: Higgins
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gendron
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rising
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Mak
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kristofor
authors.initials: K
authors.lastname: Webb
authors.affiliation: Cancer Structural Biology, Oncology Medicinal Chemistry, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Kaiser
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Zuzow
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Riviere
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Fenech
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lindsay
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, ORCRB, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Christianson
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Randolph Y
authors.initials: RY
authors.lastname: Hampton
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Wasserman
authors.affiliation: Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bennett
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D004330:Drosophila / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D054682:Ribosome Subunits, Small, Eukaryotic / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D054875:Ubiquitination; D056811:Unfolded Protein Response / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase