A combinatorial ubiquitin code degrades substrates protected by deubiquitylation
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ABSTRACT:
PROVIDER: PRJNA1141143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30015368_1.fastq.gz | Fastqsanger.gz | |||
| SRR30015368_2.fastq.gz | Fastqsanger.gz | |||
| SRR30015369_1.fastq.gz | Fastqsanger.gz | |||
| SRR30015369_2.fastq.gz | Fastqsanger.gz | |||
| SRR30015370_1.fastq.gz | Fastqsanger.gz |
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Project description:Reversibility of protein ubiquitylation play essential roles in cellular protein homeostasis. How substrates stabilized by deubiquitylation are directed for degradation remains largely elusive. Here, we show that the branched ubiquitin chains promote the degradation of the deubiquitylase (DUB) OTUD5. OTUD5 is sequentially modified by TRIP12 and UBR5, E3s specific for the K29 and K48 linkages, respectively, resulting in the conjugation of K29/K48 branched ubiquitin chains. The TRIP12-OTUD5 antagonism regulates TNF--induced NF-B signaling. Mechanistically, while OTUD5 readily cleaves K48-linkages, K29-linkages are resistant against OTUD5 activity. Consequently, K29-linkages overcome OTUD5 DUB activity to facilitate UBR5-dependent K48-linked chain branching. Regarding generality, this mechanism adopts to other TRIP12 substrates associated with OTUD5. These results uncover a cellular unique strategy in which the sequential addition of DUB-resistant and proteasome-targeting ubiquitin linkages efficiently promote degradation of substrates protected by deubiquitylation, underscoring the role of branched ubiquitin chains in the quality control of hard-to-degrade substrates.
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Project description:In Saccharomyces cerevisiae histone H2B is ubiquitylated at lysine 123. The SAGA complex component, Ubp8, is one of two proteases that remove this ubiquitin moiety. We analyzed gene expression in a strain containing a variant of histone H2B with lysine 123 converted to arginine to address the mechanisms by which ubiquitylation and deubiquitylation of histone H2B affects gene expression. We show that changes in gene expression observed upon deletion of ubp8 are suppressed by htb1K123R. This provides genetic evidence that Ubp8 alters gene expression through deubiquitylation of histone H2B. Second, microarray analyses of the htb1K123R strain show that loss of histone ubiquitylation results in a two-fold or greater change in expression of ~1.5% of the protein coding genes with greater than two-thirds increasing. For genes in which ubiquitylation represses expression, ubiquitylation principally acts through its effects on histone methylation. In contrast, decreased expression of the CWP1 gene was not paralleled by deletions of the methyltransferase components Swd3, Set2 or Dot1 and is thus likely independent of methylation. Finally, by comparing gene expression changes in the htb1K123R strain with those in a strain deleted for rad6, we conclude that lysine 123 affects transcription primarily because of its being a site of ubiquitylation. Keywords: yeast, histone ubiquitylation, Ubp8, gene expression, genetic modification, histone H2B Two dye-swapped, biological replicate experiments were performed for yeast strains CY1272(Htb1_K123R;htb2_delta0), BY10809(ubp8_delta0) and CY1383(Htb1_K123R;htb2_delta0;ubp8_delta0) with reference to BY4742(wt). Three biological replicates, including one dye-swap experiment, were performed comparing CY1272(Htb1_K123R;htb2_delta0) to BY13026(htb2_delta0).
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Project description:In Saccharomyces cerevisiae histone H2B is ubiquitylated at lysine 123. The SAGA complex component, Ubp8, is one of two proteases that remove this ubiquitin moiety. We analyzed gene expression in a strain containing a variant of histone H2B with lysine 123 converted to arginine to address the mechanisms by which ubiquitylation and deubiquitylation of histone H2B affects gene expression. We show that changes in gene expression observed upon deletion of ubp8 are suppressed by htb1K123R. This provides genetic evidence that Ubp8 alters gene expression through deubiquitylation of histone H2B. Second, microarray analyses of the htb1K123R strain show that loss of histone ubiquitylation results in a two-fold or greater change in expression of ~1.5% of the protein coding genes with greater than two-thirds increasing. For genes in which ubiquitylation represses expression, ubiquitylation principally acts through its effects on histone methylation. In contrast, decreased expression of the CWP1 gene was not paralleled by deletions of the methyltransferase components Swd3, Set2 or Dot1 and is thus likely independent of methylation. Finally, by comparing gene expression changes in the htb1K123R strain with those in a strain deleted for rad6, we conclude that lysine 123 affects transcription primarily because of its being a site of ubiquitylation. Keywords: yeast, histone ubiquitylation, Ubp8, gene expression, genetic modification, histone H2B
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