Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome)

Zenker, Martin; Mayerle, Julia; Lerch, Markus M.; Tagariello, Andreas; Zerres, Klaus; Durie, Peter R.; Beier, Matthias; Hülskamp, Georg; Guzmán, Celina Peña; Rehder, Helga; Beemer, Frits A.; Hamel, B.C.J.; Vanlieferinghen, P; Gershoni‐Baruch, Ruth; Vieira, Marta Wey; Dumić, Miroslav; Auslender, Ron; Gil-da-Silva-Lopes, Vera Lúcia; Steinlicht, Simone; Rauh, Manfred; Shalev, Stavit; Thiel, Christian T.; Winterpacht, Andreas; Kwon, Yong Tae; Varshavsky, Alexander; Reis, André

doi:10.1038/ng1681

Cited by 232 publications

(225 citation statements)

References 26 publications

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“…Johanson-Blizzard syndrome (JBS) is caused by inactivating mutations in both copies of UBR1, which encodes an N-recognin (Fig. 1A) (23,39). Clinical features of JBS are consistent with our finding that even a partial ablation of the Arg/N-end rule pathway sensitizes cells to apoptosis (Fig.…”

Section: Discussionsupporting

confidence: 77%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

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

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In the course of apoptosis, activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell. The dynamics of apoptosis involve a number of previously identified, caspase-generated proapoptotic protein fragments, defined as those that increase the probability of apoptosis. In contrast to activated caspases, which can be counteracted by inhibitor of apoptosis proteins, there is little understanding of antiapoptotic responses to proapoptotic protein fragments. One possibility is the regulation of proapoptotic fragments through their selective degradation. The previously identified proapoptotic fragments Cys-RIPK1, Cys-TRAF1, Asp-BRCA1, Leu-LIMK1, Tyr-NEDD9, Arg-BID, Asp-BCL XL , Arg-BIM EL , Asp-EPHA4, and Tyr-MET bear destabilizing N-terminal residues. Tellingly, the destabilizing nature (but not necessarily the actual identity) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution. Here, we show that these proapoptotic fragments are short-lived substrates of the Arg/N-end rule pathway. Metabolic stabilization of at least one such fragment, Cys-RIPK1, greatly augmented the activation of the apoptosis-inducing effector caspase-3. In agreement with this understanding, even a partial ablation of the Arg/N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis. We also found that caspases can inactivate components of the Arg/N-end rule pathway, suggesting a mutual suppression between this pathway and proapoptotic signaling. Together, these results identify a mechanistically specific and functionally broad antiapoptotic role of the Arg/N-end rule pathway. In conjunction with other apoptosis-suppressing circuits, the Arg/N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.

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Section: Discussionsupporting

confidence: 77%

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Piatkov

Brower

Varshavsky

2012

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

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124

195

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“…It will be important to reevaluate these proteins as possible QC substrates. In addition, a variety of phenotypes have been observed in murine nulls of several Ubr isoforms (29)(30)(31)(32); it may be that these effects are the result of deficient QC control in the affected tissues.…”

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confidence: 99%

Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1

Heck

Cheung

Hampton

2009

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

249

383

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Eukaryotic cells maintain proteostasis by quality control (QC) degradation. These pathways can specifically target a wide variety of distinct misfolded proteins, and so are important for management of cellular stress. Although a number of conserved QC pathways have been described in yeast, the E3 ligases responsible for cytoplasmic QC are unknown. We now show that Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins. This action of Ubr1 is distinct from its role in the "N-end rule." In this capacity, Ubr1 functions to protect cells from proteotoxic stresses. Our phenotypic and biochemical studies of Ubr1 and San1 indicate that two strategies are employed for cytoplasmic QC: chaperone-assisted ubiquitination by Ubr1 and chaperone-dependent delivery to nuclear San1. The broad conservation of Ubr ligases and the relevant chaperones indicates that these mechanisms will be important in understanding both basic and biomedical aspects of cellular proteostasis.chaperone | proteostasis | misfolding P rotein quality control (QC) functions to ensure that damaged and misfolded proteins are maintained at acceptable levels to limit their stress-causing, or proteotoxic, effects. One strategy of protein QC is the selective degradation of misfolded proteins. For degradative QC pathways to be effective, they must be specific for aberrant proteins; sufficiently general to recognize selectively common structural hallmarks shared by numerous unrelated proteins; and physiologically important, better allowing the cell to survive proteotoxic stress. Because protein QC underlies many pressing maladies, such as parkinsonism, cystic fibrosis, and aging, discovery of the rules of substrate selectivity and destruction is a key step in understanding these conditions and designing appropriate therapeutical interventions to combat them.In eukaryotes, the ubiquitin proteasome system is employed in the selective degradation of many proteins (1). A substrate protein is marked for degradation by assembly of a polyubiquitin chain, initiated by covalent addition of the small (7.6 kDa) protein ubiquitin to a lysine in an isopeptide bond, followed by iterative addition of the next ubiquitin to the previously added one to create a polyubiquitin chain that is uniquely recognized by the 26S proteasome. Protein ubiquitination is catalyzed by a three-enzyme cascade. The single E1 ubiquitin-activating enzyme hydrolyzes ATP to acquire ubiquitin in labile thioester linkage, which is then transferred in thioester linkage to one of a small group of E2s or ubiquitin-conjugating enzymes (UBCs). E2-bound ubiquitin is finally transferred to an isopeptide linkage on the target protein or the growing polyubiquitin chain by the action of the E3 ubiquitin ligase. It is the E3 ubiquitin ligase that determines the specificity of a given ubiquitination process; identifying and understanding the E3s involved in a degradative pathway are thus key parts of understanding the mechanisms of substrate selection and modification.E3s ...

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“…1A) (25,39), are the cause of JohansonBlizzard syndrome, which includes mental retardation, physical malformations, and severe pancreatitis (54). The abnormalities of UBR1 Ϫ/Ϫ mice (38) include pancreatic insufficiency (54), a less severe version of the defect in human Johanson-Blizzard syndrome (UBR1 Ϫ/Ϫ ) patients. The cardiovascular and (probably) other functions of the N-end rule pathway involve the arginylation-mediated degradation of RGS4, RGS5, and RGS16.…”

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confidence: 99%

Arginyltransferase, Its Specificity, Putative Substrates, Bidirectional Promoter, and Splicing-derived Isoforms

Brower

Wang

et al. 2006

Journal of Biological Chemistry

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106

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Substrates of the N-end rule pathway include proteins with destabilizing N-terminal residues. Three of them, Asp, Glu, and (oxidized) Cys, function through their conjugation to Arg, one of destabilizing N-terminal residues that are recognized directly by the pathway's ubiquitin ligases. The conjugation of Arg is mediated by arginyltransferase, encoded by ATE1. Through its regulated degradation of specific proteins, the arginylation branch of the N-end rule pathway mediates, in particular, the cardiovascular development, the fidelity of chromosome segregation, and the control of signaling by nitric oxide. We show that mouse ATE1 specifies at least six mRNA isoforms, which are produced through alternative splicing, encode enzymatically active arginyltransferases, and are expressed at varying levels in mouse tissues. We also show that the ATE1 promoter is bidirectional, mediating the expression of both ATE1 and an oppositely oriented, previously uncharacterized gene. In addition, we identified GRP78 (glucose-regulated protein 78) and protein-disulfide isomerase as putative physiological substrates of arginyltransferase. Purified isoforms of arginyltransferase that contain the alternative first exons differentially arginylate these proteins in extract from ATE1 ؊/؊ embryos, suggesting that specific isoforms may have distinct functions. Although the N-end rule pathway is apparently confined to the cytosol and the nucleus, and although GRP78 and protein-disulfide isomerase are located largely in the endoplasmic reticulum, recent evidence suggests that these proteins are also present in the cytosol and other compartments in vivo, where they may become N-end rule substrates.A protein substrate of the ubiquitin (Ub) 2 -proteasome system, which controls the levels of many intracellular proteins, is conjugated to Ub through the action of ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) (1-7). The term "Ub ligase" denotes either an E2-E3 holoenzyme or its E3 component. The selectivity of ubiquitylation is mediated largely by E3, which recognizes a degradation signal (degron) of a substrate (1, 3, 8 -12). The E3 Ub ligases are an exceptionally large family, with more than 500 distinct E3s in a mammal (5,(12)(13)(14). A ubiquitylated protein bears a covalently linked poly-Ub chain and is targeted for processive degradation by the 26 S proteasome (15)(16)(17)(18)(19). Ub has other functions as well, including nonproteolytic ones (20,21).An essential determinant of one class of degrons, called N-degrons, is a destabilizing N-terminal residue of a substrate. The set of destabilizing residues in a given cell type yields a rule, called the N-end rule, which relates the in vivo half-life of a protein to the identity of its N-terminal residue (1,(22)(23)(24)(25)(26). In eukaryotes, the N-degron consists of three determinants: a destabilizing N-terminal residue of a protein substrate, its internal Lys residue(s) (the site of formation of a poly-Ub chain), and a conformationally fl...

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Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome)

Cited by 232 publications

References 26 publications

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments

Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1

Arginyltransferase, Its Specificity, Putative Substrates, Bidirectional Promoter, and Splicing-derived Isoforms

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