Dynamic Sumoylation of a Conserved Transcription Corepressor Prevents Persistent Inclusion Formation during Hyperosmotic Stress

Oeser, Michelle L.; Amen, Triana; Nadel, Cory M.; Bradley, Amanda I.; Reed, Benjamin J.; Jones, Ramon D.; Gopalan, Janani; Kaganovich, Daniel; Gardner, Richard G.

doi:10.1371/journal.pgen.1005809

Cited by 19 publications

(54 citation statements)

References 78 publications

(128 reference statements)

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“…S1A and Dataset S1), such as the transcriptional activators Gcn4 and Rap1 and the transcriptional repressors Tup1 and Cyc8 (Fig. 1B), which we and others have previously shown to be SUMO targets (10)(11)(12). The vast majority of proteins in group 2 are involved in cellular processes that ultimately impinge upon mRNA translation ( Fig.…”

Section: Significancementioning

confidence: 86%

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TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

Chymkowitch

Aanes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Maintaining cellular homeostasis under changing nutrient conditions is essential for the growth and development of all organisms. The mechanisms that maintain homeostasis upon loss of nutrient supply are not well understood. By mapping the SUMO proteome in Saccharomyces cerevisiae, we discovered a specific set of differentially sumoylated proteins mainly involved in transcription. RNA polymerase III (RNAPIII) components, including Rpc53, Rpc82, and Ret1, are particularly prominent nutrient-dependent SUMO targets. Nitrogen starvation, as well as direct inhibition of the master nutrient response regulator target of rapamycin complex 1 (TORC1), results in rapid desumoylation of these proteins, which is reflected by loss of SUMO at tRNA genes. TORC1-dependent sumoylation of Rpc82 in particular is required for robust tRNA transcription. Mechanistically, sumoylation of Rpc82 is important for assembly of the RNAPIII holoenzyme and recruitment of Rpc82 to tRNA genes. In conclusion, our data show that TORC1-dependent sumoylation of Rpc82 bolsters the transcriptional capacity of RNAPIII under optimal growth conditions.I n yeast and in more complex eukaryotes, cell growth is restricted by the rate of mRNA translation and ribosome biogenesis, which depend on the transcription of ribosomal protein genes (RPGs), tRNAs and rRNAs. Synthesis of rRNA, tRNAs, and 5S rRNA represents 75% of total cellular transcription, whereas transcription of RPGs corresponds to 50% of RNA polymerase II (RNAPII) initiation events (1). These processes consume a significant portion of the cell's resources, making nutrient availability a limiting factor to cell growth and proliferation (2). The conserved rapamycin-sensitive target of rapamycin complex 1 (TORC1) is a master regulator of the cellular nutrient response (2, 3). Under nitrogen-rich conditions, TORC1 promotes growth-related processes, like protein synthesis, ribosome biogenesis, and tRNA synthesis, while inhibiting catabolic processes, like autophagy (2). Conversely, inhibition of TORC1 activity by nitrogen depletion (or addition of the TORC1 inhibitor rapamycin) results in a metabolic switch from anabolism to catabolism, which involves many cellular processes, including down-regulation of transcription of RPGs, rRNA and tRNA genes (2, 3).A key downstream target of TORC1 in regulation of tRNA transcription is the conserved RNAPIII inhibitor Maf1, which is phosphorylated and maintained in the cytoplasm under nitrogenrich conditions (2, 3). Maf1 becomes hypophosphorylated under conditions that inhibit TORC1, allowing it to enter the nucleus where it associates with TFIIIB. The interaction between Maf1 and TFIIIB prevents the recruitment of RNAPIII and precludes transcription reinitiation at 5S rRNA and tRNA genes (4, 5). However, expression of an unphosphorylatable maf1 mutant does not completely repress tRNA expression in nutrient-replete cells (6), suggesting that dephosphorylation of Maf1 alone is not sufficient to fully inhibit RNAPIII. Indeed, inhibition of TORC1 also results in phospho...

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Section: Significancementioning

confidence: 86%

“…Pull-downs in denaturing conditions were performed as previously described (10,11,29) with minor modifications (SI Methods).…”

Section: Methodsmentioning

confidence: 99%

TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

Chymkowitch

Aanes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…A few examples include the ability of sumoylation to prevent protein inclusions formed by the transcriptional corepressor subunit Cyc8, to solubilize DNA end resection protein Sae2, and to reduce aggregation of translation factor CPEB3 or transcription factor androgen receptor (Drisaldi et al, 2015; Mukherjee et al, 2009; Oeser et al, 2016; Sarangi et al, 2015). Future study on how SUMO contributes to the dynamic assembly and disassembly of other proteinaceous and membraneless structures will expand our understanding of the structural roles of SUMO.…”

Section: Sumo Affects Nuclear Structures and Functionsmentioning

confidence: 99%

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

2018

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Summary Since the discovery of SUMO twenty years ago, SUMO conjugation has become a widely-recognized post-translational modification that targets a myriad of proteins in many processes. Great progress has been made in understanding the SUMO pathway enzymes, substrate sumoylation, and the interplay between sumoylation and other regulatory mechanisms in a variety of contexts. As these research directions continue to generate insights into SUMO-based regulation, several mechanisms by which sumoylation and desumoylation can orchestrate large biological effects are emerging. These include the ability to target multiple proteins within the same cellular structure or process, respond dynamically to external and internal stimuli, and modulate signaling pathways involving other post-translational modifications. Focusing on nuclear function and intracellular signaling, this review highlights a broad spectrum of historical data and recent advances with the aim of providing an overview of mechanisms underlying SUMO-mediated global effects to stimulate further inquiry into intriguing roles of SUMO.

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“…Interestingly, Gardner and coworkers recently showed that the conserved transcriptional corepressor Cyc8 is SUMOylated upon hyperosmotic stress in yeast (94). Loss of Cyc8 SUMOylation leads to cytoplasmic inclusion formation of this protein.…”

Section: Sumoylation Regulates Proteostasis At the Chromatin Levelmentioning

confidence: 99%

“…Loss of Cyc8 SUMOylation leads to cytoplasmic inclusion formation of this protein. Thus, SUMO acts to maintain the proper function of Cyc8 during hyperosmotic stress (94). This provides an interesting example of the role of SUMO during stress to maintain the solubility and thereby the function of these proteins.…”

Section: Sumoylation Regulates Proteostasis At the Chromatin Levelmentioning

confidence: 99%

Ubiquitin-dependent and independent roles of SUMO in proteostasis

Liebelt

Vertegaal

2016

American Journal of Physiology-Cell Physiology

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Cellular proteomes are continuously undergoing alterations as a result of new production of proteins, protein folding, and degradation of proteins. The proper equilibrium of these processes is known as proteostasis, implying that proteomes are in homeostasis. Stress conditions can affect proteostasis due to the accumulation of misfolded proteins as a result of overloading the degradation machinery. Proteostasis is affected in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple polyglutamine disorders including Huntington's disease. Owing to a lack of proteostasis, neuronal cells build up toxic protein aggregates in these diseases. Here, we review the role of the ubiquitin-like posttranslational modification SUMO in proteostasis. SUMO alone contributes to protein homeostasis by influencing protein signaling or solubility. However, the main contribution of SUMO to proteostasis is the ability to cooperate with, complement, and balance the ubiquitin-proteasome system at multiple levels. We discuss the identification of enzymes involved in the interplay between SUMO and ubiquitin, exploring the complexity of this crosstalk which regulates proteostasis. These enzymes include SUMO-targeted ubiquitin ligases and ubiquitin proteases counteracting these ligases. Additionally, we review the role of SUMO in brain-related diseases, where SUMO is primarily investigated because of its role during formation of aggregates, either independently or in cooperation with ubiquitin. Detailed understanding of the role of SUMO in these diseases could lead to novel treatment options.

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Dynamic Sumoylation of a Conserved Transcription Corepressor Prevents Persistent Inclusion Formation during Hyperosmotic Stress

Cited by 19 publications

References 78 publications

TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

TORC1-dependent sumoylation of Rpc82 promotes RNA polymerase III assembly and activity

SUMO-Mediated Regulation of Nuclear Functions and Signaling Processes

Ubiquitin-dependent and independent roles of SUMO in proteostasis

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