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OTUD6 deubiquitination of RPS7/eS7 on the free 40S ribosome regulates protein translation and the response to stress

ABSTRACT: The life cycle of the ribosome is highly regulated by ubiquitination and deubiquitination events that are remarkably well conserved across the evolutionary scale. We uncover the role of the ovarian tumor (OTU)-class deubiquitinase OTUD6 in setting the level of protein translation by deubiquitination of the RPS7/eS7 subunit of the 40S ribosome in vivo in Drosophila, using endogenously tagged wild-type and mutant proteins. Coimmunoprecipitation and enrichment of monoubiquitinated proteins from catalytically inactive OTUD6 flies revealed the 40S ribosomal protein RPS7 as the major OTUD6 ribosomal substrate. OTUD6 genetically interacts with the 40S protein RACK1 and the ubiquitin E3 ligases CNOT4 and RNF10 to set alkylation stress sensitivity by regulating the level of RPS7 monoubiquitination. OTUD6 specifically interacts with RPS7 on the free 40S subunit, and not on translation initiation complexes or the 80S translating ribosome. Moreover, mRNAs are depleted of free 40S ribosomal subunits in catalytically inactive OTUD6 flies. OTUD6 bidirectionally promotes the global level of protein translation through its action on RPS7. OTUD6 protein is itself regulated by different physiological conditions and stressors to lower the level of RPS7 monoubiquitination and increase the level of protein translation. We propose that OTUD6 promotes translation initiation, the rate limiting step in protein translation, by titering the availability of 40S subunits for forming the 43S preinitiation complex.

INSTRUMENT(S): Orbitrap Eclipse, Orbitrap Fusion Lumos

ORGANISM(S): Drosophila <fruit Fly, Genus> (ncbitaxon:7215)

SUBMITTER: Christopher Rose

PROVIDER: MSV000091040 | MassIVE | Tue Jan 10 15:37:00 GMT 2023

REPOSITORIES: MassIVE

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