Journal article
OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress
Nature communications, Vol.15(1), 6873
08/11/2024
DOI: 10.1038/s41467-024-51284-y
PMCID: PMC11316749
PMID: 39127721
Abstract
Ribosomes are regulated by evolutionarily conserved ubiquitination/deubiquitination events. We uncover the role of the deubiquitinase OTUD6 in regulating global protein translation through deubiquitination of the RPS7/eS7 subunit on the free 40 S ribosome in vivo in Drosophila. Coimmunoprecipitation and enrichment of monoubiquitinated proteins from catalytically inactive OTUD6 flies reveal RPS7 as the ribosomal substrate. The 40 S protein RACK1 and E3 ligases CNOT4 and RNF10 function upstream of OTUD6 to regulate alkylation stress. OTUD6 interacts with RPS7 specifically on the free 40 S, and not on 43 S/48 S initiation complexes or the translating ribosome. Global protein translation levels are bidirectionally regulated by OTUD6 protein abundance. OTUD6 protein abundance is physiologically regulated in aging and in response to translational and alkylation stress. Thus, OTUD6 may promote translation initiation, the rate limiting step in protein translation, by titering the amount of 40 S ribosome that recycles.Ribosomes are regulated by evolutionarily conserved ubiquitination/deubiquitination events. We uncover the role of the deubiquitinase OTUD6 in regulating global protein translation through deubiquitination of the RPS7/eS7 subunit on the free 40 S ribosome in vivo in Drosophila. Coimmunoprecipitation and enrichment of monoubiquitinated proteins from catalytically inactive OTUD6 flies reveal RPS7 as the ribosomal substrate. The 40 S protein RACK1 and E3 ligases CNOT4 and RNF10 function upstream of OTUD6 to regulate alkylation stress. OTUD6 interacts with RPS7 specifically on the free 40 S, and not on 43 S/48 S initiation complexes or the translating ribosome. Global protein translation levels are bidirectionally regulated by OTUD6 protein abundance. OTUD6 protein abundance is physiologically regulated in aging and in response to translational and alkylation stress. Thus, OTUD6 may promote translation initiation, the rate limiting step in protein translation, by titering the amount of 40 S ribosome that recycles.
Details
- Title: Subtitle
- OTUD6 deubiquitination of RPS7/eS7 on the free 40 S ribosome regulates global protein translation and stress
- Creators
- Sammy Villa - University of California, MercedPankaj Dwivedi - United States Military AcademyAaron Stahl - University of Iowa, Neuroscience and PharmacologyTrent HinkleChristopher M RoseDonald S KirkpatrickSeth M Tomchik - University of IowaVishva M DixitFred W Wolf - University of California, Merced
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.15(1), 6873
- Publisher
- NATURE PORTFOLIO
- DOI
- 10.1038/s41467-024-51284-y
- PMID
- 39127721
- PMCID
- PMC11316749
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- Genentech (Genentech, Inc.): R01NS124716, R01NS114403
We thank Neha Kachewar for help with dual drug treatment experiments and genotyping for RPS7 CRISPR editing. Genentech Contract (FWW), R01NS124716 and R01NS114403 (SMT).DAS:All data needed to evaluate the conclusions in the paper are present in the Source Data file and in the Supplementary Information and Data files. Raw data from mass spectrometry were deposited within the MassIVE repository under the identifier MSV000091040. Drosophila strains created in this study are deposited at the Bloomington Drosophila Stock Center. Source data are provided with this paper.
- Language
- English
- Date published
- 08/11/2024
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984696855002771
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