Rhes, a striatal enriched protein, regulates SUMOylation of nuclear proteins and gene expression in a SUMO-dependent manner
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ABSTRACT:
PROVIDER: PRJNA634335 | ENA |
REPOSITORIES: ENA
Dataset's files
primary
| Action | DRS | |||
|---|---|---|---|---|
| SRR11825850_1.fastq.gz | Fastqsanger.gz | |||
| SRR11825850_2.fastq.gz | Fastqsanger.gz | |||
| SRR11825851_1.fastq.gz | Fastqsanger.gz | |||
| SRR11825851_2.fastq.gz | Fastqsanger.gz | |||
| SRR11825852_1.fastq.gz | Fastqsanger.gz |
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Project description:SUMOylation is a reversible post-translational modification essential for genome stability. Using high-resolution MS, we have studied global SUMOylation in human cells in a site-specific manner, identifying a total of >4,300 SUMOylation sites in >1,600 proteins. To our knowledge, this is the first time that >1,000 SUMOylation sites have been identified under standard growth conditions. We quantitatively studied SUMOylation dynamics in response to SUMO protease inhibition, proteasome inhibition and heat shock. Many SUMOylated lysines have previously been reported to be ubiquitinated, acetylated or methylated, thus indicating cross-talk between SUMO and other post-translational modifications. We identified 70 phosphorylation and four acetylation events in proximity to SUMOylation sites, and we provide evidence for acetylation-dependent SUMOylation of endogenous histone H3. SUMOylation regulates target proteins involved in all nuclear processes including transcription, DNA repair, chromatin remodeling, precursor-mRNA splicing and ribosome assembly.
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Project description:Caveolin (Cav) proteins in the plasma membrane have numerous binding partners, but the determinants of these interactions are poorly understood. We show here that Cav-3 has a small ubiquitin-like modifier (SUMO) consensus motif (?KX(D/E, where ? is a hydrophobic residue)) near the scaffolding domain and that Cav-3 is SUMOylated in a manner that is enhanced by the SUMO E3 ligase PIASy (protein inhibitor of activated STAT-y). Site-directed mutagenesis revealed that the consensus site lysine is the preferred SUMOylation site but that mutation of all lysines is required to abolish SUMOylation. Co-expression of a SUMOylation-deficient mutant of Cav-3 with ?-adrenergic receptors (?ARs) alters the expression level of ?(2)ARs but not ?(1)ARs following agonist stimulation, thus implicating Cav-3 SUMOylation in the mechanisms for ?(2)AR but not ?(1)AR desensitization. Expression of endothelial nitric-oxide synthase (NOS3) was not altered by the SUMOylation-deficient mutant. Thus, SUMOylation is a covalent modification of caveolins that influence the regulation of certain signaling partners.
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Project description:The ubiquitin-like protein SUMO is transferred through a core E1-E2 cascade composed of the SUMO-activating enzyme (SAE) and Ubc9 to modify cellular proteins and transmit important biological signals. SAE primarily recognizes the C-terminal tail of SUMO and catalyzes ATP condensation with the SUMO C-terminal carboxylate to activate its transfer through the cascade. Here, we used phage display to show that a broad profile of SUMO C-terminal sequences could be activated by SAE. Based on this, we developed heptamer peptides that could 1) form thioester conjugates with SAE, 2) be transferred from SAE to Ubc9, and 3) be further transferred to the SUMOylation target protein RanGAP1. As these peptides recapitulate the action of SUMO in protein modification, we refer to them as "SUMO-mimicking peptides". We found that, once the peptides were conjugated to SAE and Ubc9, they blocked full-length SUMO from entering the cascade. These peptides can thus function as mechanism-based inhibitors of the protein SUMOylation reaction.
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Project description:Small ubiquitin-like modifiers (SUMOs) regulate a variety of cellular processes through two distinct mechanisms, including covalent sumoylation and non-covalent SUMO interaction. The complexity of SUMO regulations has greatly hampered the large-scale identification of SUMO substrates or interaction partners on a proteome-wide level. In this work, we developed a new tool called GPS-SUMO for the prediction of both sumoylation sites and SUMO-interaction motifs (SIMs) in proteins. To obtain an accurate performance, a new generation group-based prediction system (GPS) algorithm integrated with Particle Swarm Optimization approach was applied. By critical evaluation and comparison, GPS-SUMO was demonstrated to be substantially superior against other existing tools and methods. With the help of GPS-SUMO, it is now possible to further investigate the relationship between sumoylation and SUMO interaction processes. A web service of GPS-SUMO was implemented in PHP+JavaScript and freely available at http://sumosp.biocuckoo.org.
2014-01-01 | S-EPMC4086084 | BioStudies
Project description:SUMOylation is a transient posttranslational modification with small-ubiquitin like modifiers (SUMO1, SUMO2 and SUMO3) covalently attached to their target-proteins via a multi-step enzymatic cascade. SUMOylation modifies protein-protein interactions, enzymatic-activity or chromatin binding in a multitude of key cellular processes, acting as a highly dynamic molecular switch. To guarantee the rapid kinetics, SUMO target-proteins are kept in a tightly controlled equilibrium of SUMOylation and deSUMOylation. DeSUMOylation is maintained by the SUMO-specific proteases, predominantly of the SENP family. SENP1 and SENP2 represent family members tuning SUMOylation status of all three SUMO isoforms, while SENP3 and SENP5 are dedicated to detach mainly SUMO2/3 from its substrates. SENP6 and SENP7 cleave polySUMO2/3 chains thereby countering the SUMO-targeted-Ubiquitin-Ligase (StUbL) pathway. Several biochemical studies pinpoint towards the SENPs as critical enzymes to control balanced SUMOylation/deSUMOylation in cardiovascular health and disease. This study aims to review the current knowledge about the SUMO-specific proteases in the heart and provides an integrated view of cardiac functions of the deSUMOylating enzymes under physiological and pathological conditions.
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Project description:SUMO, a small ubiquitin-related modifier, is known to covalently attach to a number of nuclear regulatory proteins such as p53, IkappaB, promyelocytic leukemia protein and c-Jun. The sumoylation reaction is catalyzed by the SUMO protease, which exposes the C-terminal active glycine residue of the nascent SUMO, the heterodimeric SUMO activating enzyme, the SUMO conjugating enzyme, Ubc9, and SUMO protein ligases, in a manner similar to ubiquitinylation. Identification of SUMO-regulated proteins is hampered by the fact that many sumoylated proteins are present at a level below normal detection limit. This limitation was overcome by either in vivo overexpression of Myc-SUMO or in vitro sumoylation with excess biotin-SUMO and Ubc9. Sumoylated proteins so obtained were affinity purified or isolated by immunoprecipitation. The isolated sumoylated proteins were identified by sequence analysis using mass spectrometric methods. Results reveal that several heterogeneous nuclear ribonucleoproteins (hnRNPs), zinc finger proteins, and nuclear pore complex proteins were sumoylated. The sumoylation of hnRNP A1, hnRNP F, and hnRNP K were confirmed in vivo by coimmunoprecipitation. In view of the facts that hnRNPs have been implicated in RNA splicing, transport, stability, and translation, our findings suggest that sumoylation could play an important role in regulating mRNA metabolism.
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Project description:Sumoylation, the reversible covalent attachment of small ubiquitin-like modifier (SUMO) peptides has emerged as an important regulator of target protein function. In Saccharomyces cerevisiae, but not in Schizosaccharyomes pombe, deletion of the gene encoding SUMO peptides is lethal. We have characterized the SUMO-encoding gene, sumO, in the filamentous fungus Aspergillus nidulans. The sumO gene was deleted in a diploid and sumODelta haploids were recovered. The mutant was viable but exhibited impaired growth, reduced conidiation and self-sterility. Overexpression of epitope-tagged SumO peptides revealed multiple sumoylation targets in A. nidulans and SumO overexpression resulted in greatly increased levels of protein sumoylation without obvious phenotypic consequences. Using five-piece fusion PCR, we generated a gfp-sumO fusion gene expressed from the sumO promoter for live-cell imaging of GFP-SumO and GFP-SumO-conjugated proteins. Localization of GFP-SumO is dynamic, accumulating in punctate spots within the nucleus during interphase, lost at the onset of mitosis and re-accumulating during telophase.
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Project description:Regulation of transcription is fundamental to the control of cellular gene expression and function. Although recent studies have revealed a role for the oncoprotein MYC in amplifying global transcription, little is known as to how the global transcription is suppressed. Here we report that SUMO and MYC mediate opposite effects upon global transcription by controlling the level of CDK9 sumoylation. On one hand, SUMO suppresses global transcription via sumoylation of CDK9, the catalytic subunit of P-TEFb kinase essential for productive transcriptional elongation. On the other hand, MYC amplifies global transcription by antagonizing CDK9 sumoylation. Sumoylation of CDK9 blocks its interaction with Cyclin T1 and thus the formation of active P-TEFb complex. Transcription profiling analyses reveal that SUMO represses global transcription, particularly of moderately to highly expressed genes and by generating a sumoylation-resistant CDK9 mutant, we confirm that sumoylation of CDK9 inhibits global transcription. Together, our data reveal that SUMO and MYC oppositely control global gene expression by regulating the dynamic sumoylation and desumoylation of CDK9.
2018-01-01 | S-EPMC5993822 | BioStudies
Project description:The Srs2 DNA helicase of Saccharomyces cerevisiae affects recombination in multiple ways. Srs2 not only inhibits recombination at stalled replication forks but also promotes the synthesis-dependent strand annealing (SDSA) pathway of recombination. Both functions of Srs2 are regulated by sumoylation--sumoylated PCNA recruits Srs2 to the replication fork to disfavor recombination, and sumoylation of Srs2 can be inhibitory to SDSA in certain backgrounds. To understand Srs2 function, we characterize the mechanism of its sumoylation in vitro and in vivo. Our data show that Srs2 is sumoylated at three lysines, and its sumoylation is facilitated by the Siz SUMO ligases. We also show that Srs2 binds to SUMO via a C-terminal SUMO-interacting motif (SIM). The SIM region is required for Srs2 sumoylation, likely by binding to SUMO-charged Ubc9. Srs2's SIM also cooperates with an adjacent PCNA-specific interaction site in binding to sumoylated PCNA to ensure the specificity of the interaction. These two functions of Srs2's SIM exhibit a competitive relationship: sumoylation of Srs2 decreases the interaction between the SIM and SUMO-PCNA, and the SUMO-PCNA-SIM interaction disfavors Srs2 sumoylation. Our findings suggest a potential mechanism for the equilibrium of sumoylated and PCNA-bound pools of Srs2 in cells.
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Project description:Small ubiquitin-like modifier (SUMO) E3 ligases are known to have a major role in preventing gross chromosomal rearrangements (GCRs); however, relatively little is known about the role of SUMO isopeptidases in genome maintenance and their role in controlling intracellular sumoylation homeostasis. Here we show the SUMO isopeptidase Ulp2 in Saccharomyces cerevisiae does not prevent the accumulation of GCRs, and interestingly, its loss causes subunit-specific changes of sumoylated minichromosome maintenance (MCM) helicase in addition to drastic accumulation of sumoylated nucleolar RENT and inner kinetochore complexes. In contrast, loss of Ulp1 or its mis-localization from the nuclear periphery causes substantial accumulations of GCRs and elevated sumoylation of most proteins except for Ulp2 targets. Interestingly, the E3 ligase Mms21, which has a major role in genome maintenance, preferentially controls the sumoylation of Mcm3 during DNA replication. These findings reveal distinct roles for Ulp1 and Ulp2 in controlling homeostasis of intracellular sumoylation and show that sumoylation of MCM is controlled in a subunit-specific and cell cycle dependent manner.
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