Ubiquitin chains in the Dsk2 UBL domain mediate Dsk2 stability and protein degradation in yeast

Sekiguchi, Toshio; Sasaki, Toru; Funakoshi, Mitsuaki; Ishii, Takashi; Saitoh, Yoh hei; Kaneko, Shu ichi; Kobayashi, Hideki

doi:10.1016/j.bbrc.2011.06.183

Cited by 6 publications

(6 citation statements)

References 24 publications

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“…It has been proposed that the presence of several ubiquitin shuttle factors with different, though partially overlapping, specificities might function as a regulatory layer that determines the targeting rate of distinct pools of substrate (Verma et al, 2004). Although there are some examples of post-translational modifications and binding proteins that regulate the interaction of ubiquitin shuttle factors with the proteasome (Isasa et al, 2010;Liang et al, 2014;Sekiguchi et al, 2011), it is presently unclear if and how these processes are regulated by internal and/or external cues. It is feasible that, under certain conditions, Rad23 deubiquitylation behaves as a regulatory switch that stalls degradation of Rad23-dependent substrates, thereby giving higher priority to substrates that reach the proteasome by different means, such as alternative shuttle factors.…”

Section: Discussionmentioning

confidence: 99%

“…Second, post-translational modifications may change the behavior of the ubiquitin shuttle factors and may provide a means to control their activity. Notably, phosphorylation of the UbL domain of Rad23 regulates its interaction with the proteasome (Liang et al, 2014), while modification of Dsk2 with proteolytic ubiquitin chains results in a reduced capacity to bind polyubiquitylated proteins (Sekiguchi et al, 2011). Moreover, recruitment of the ubiquitin-binding receptor Rpn10 is regulated by monoubiquitylation (Isasa et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation

Gödderz

Giovannucci

Laláková

et al. 2017

Journal of Cell Science

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The consecutive actions of the ubiquitin-selective segregase Cdc48 and the ubiquitin shuttle factor Rad23 result in the delivery of ubiquitylated proteins at the proteasome. Here, we show that the deubiquitylating enzyme Ubp12 interacts with Cdc48 and regulates proteasomal degradation of Rad23-dependent substrates in Overexpression of Ubp12 results in stabilization of Rad23-dependent substrates. We show that Ubp12 removes short ubiquitin chains from the N-terminal ubiquitin-like domain (UbL) of Rad23. Preventing ubiquitylation of Rad23 by mutation of lysine residues within the UbL domain, Rad23, does not affect the non-proteolytic role of Rad23 in DNA repair but causes an increase in ubiquitylated cargo bound to the UBA2 domain of Rad23, recapitulating the stabilization of Rad23-dependent substrates observed upon overexpression of Ubp12. Expression of Rad23 or overexpression of Ubp12 impairs the ability of yeast to cope with proteotoxic stress, consistent with inefficient clearance of misfolded proteins by the ubiquitin-proteasome system. Our data suggest that ubiquitylation of Rad23 plays a stimulatory role in the degradation of ubiquitylated substrates by the proteasome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation

Gödderz

Giovannucci

Laláková

et al. 2017

Journal of Cell Science

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“…As described below, Rad23 participates in the nucleotide excision repair (NER) pathway of DNA repair. Finally, mutated variants of the shuttling receptors have been studied as unique model substrates of the proteasome, although their wild-type forms are relatively stable (Heessen et al 2005;Fishbain et al 2011;Heinen et al 2011;Sekiguchi et al 2011) Deubiquitylation at the proteasome: The lid is positioned for the most part laterally to the base, and its subunits extend like fingers to contact the base at many points ( Figure 5C; Lander et al 2012;Lasker et al 2012). A key function of the lid is to deubiquitylate proteasome substrates, an activity mediated by its subunit Rpn11 (Maytal-Kivity et al 2002;Verma et al 2002;Yao and Cohen 2002).…”

Section: Regulatory Particlementioning

confidence: 99%

The Ubiquitin–Proteasome System of Saccharomyces cerevisiae

et al. 2012

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Protein modifications provide cells with exquisite temporal and spatial control of protein function. Ubiquitin is among the most important modifiers, serving both to target hundreds of proteins for rapid degradation by the proteasome, and as a dynamic signaling agent that regulates the function of covalently bound proteins. The diverse effects of ubiquitylation reflect the assembly of structurally distinct ubiquitin chains on target proteins. The resulting ubiquitin code is interpreted by an extensive family of ubiquitin receptors. Here we review the components of this regulatory network and its effects throughout the cell.

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“…Hence, the lysine desert in RAD23A appears not to be essential to protect from degradation but is still necessary for function. One possible explanation may be that ubiquitylation of lysine residues in the UBL domain of RAD23A seems to be required for function, but without affecting its degradation 49,50 . Modification at other lysine residues on the other hand may interfere with downstream signaling or act as a competitive acceptor for incoming ubiquitin.…”

Section: Discussionmentioning

confidence: 99%

Lysine deserts prevent adventitious ubiquitylation of ubiquitin-proteasome components

Kampmeyer

Grønbæk-Thygesen

Oelerich

et al. 2022

Preprint

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In terms of its relative frequency, lysine is a common amino acid in the human proteome. However, by bioinformatics we find hundreds of proteins that contain long and evolutionarily conserved stretches completely devoid of lysine residues. These so-called lysine deserts show a high prevalence in intrinsically disordered proteins with known or predicted functions within the ubiquitin-proteasome system (UPS), including many E3 ubiquitin-protein ligases and UBL domain proteasome substrate shuttles, such as BAG6, RAD23A, UBQLN1 and UBQLN2. We show that introduction of lysine residues into the deserts leads to a striking increase in ubiquitylation of some of these proteins. In case of BAG6, we show that ubiquitylation is catalyzed by the E3 RNF126, while RAD23A is ubiquitylated by E6AP. Despite the elevated ubiquitylation, mutant RAD23A appears stable, but displays a partial loss of function phenotype in fission yeast. In case of UBQLN1 and BAG6, introducing lysine leads to a reduced abundance due to proteasomal degradation of the proteins. For UBQLN1 we show that arginine residues within the lysine depleted region are critical for its ability to form cytosolic inclusions. We propose that selective pressure to avoid lysine residues may be a common evolutionary mechanism to prevent unwarranted ubiquitylation and/or perhaps other lysine post-translational modifications. This may be particularly relevant for UPS components as they closely and frequently encounter the ubiquitylation machinery and are thus more susceptible to non-specific ubiquitylation.

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Ubiquitin chains in the Dsk2 UBL domain mediate Dsk2 stability and protein degradation in yeast

Cited by 6 publications

References 24 publications

The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation

The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation

The Ubiquitin–Proteasome System of Saccharomyces cerevisiae

Lysine deserts prevent adventitious ubiquitylation of ubiquitin-proteasome components

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