The Differential Modulation of USP Activity by Internal Regulatory Domains, Interactors and Eight Ubiquitin Chain Types

Faesen, Alex C.; Luna-Vargas, Mark P.A.; Geurink, Paul P.; Clerici, Marcello; Merkx, Remco; Dijk, Willem J. van; Hameed, Dharjath S.; Oualid, Farid El; Ovaa, Huib; Sixma, Titia K.

doi:10.1016/j.chembiol.2011.10.017

Cited by 191 publications

(236 citation statements)

References 59 publications

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“…In contrast to the other DUBs families, such as the OTU DUBs (40), most of the members of the USP family have been reported to display a promiscuous deubiquitinating activity preference in an assay against the eight possible diubiquitin linkages (39). An exception to this is the tumor suppressor CYLD, which possesses specific deubiquitinating activity for Lys 63 -linked ubiquitin chains synthesized in response to cytokine-mediated activation of TRAF2 and TRAF3 ubiquitin E3 ligases, thus antagonizing NF-B signaling (13).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

Zhen

Knobel

Stracker

et al. 2014

Journal of Biological Chemistry

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Background: USP28 is a deubiquitinating enzyme implicated in the DNA damage response, Myc stabilization, and cancer progression. Results: USP28 activity is regulated by SUMO conjugation on the N-terminal region. Conclusion:The N-terminal ubiquitin-binding domains of USP28 are not required for polyubiquitin processing. Significance: Cross-talk exists between SUMO and ubiquitin in the regulation of USP28 enzymatic activity.

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Section: Discussionmentioning

confidence: 99%

“…A previous report with several USP proteins, which includes the homologous USP25, showed only minor differences against all eight diubiquitin substrates (39). In contrast, the deubiquitinating activity of USP28 against diubiquitin linkages resembles the OTU DUB family, where members are specific for one or a small subset of diubiquitin linkages types (40).…”

mentioning

confidence: 99%

Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

Zhen

Knobel

Stracker

et al. 2014

Journal of Biological Chemistry

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“…In general, while the USP family of proteins displays variations in k cat and K m over orders of magnitude, they exhibit little specificity for particular isopeptide chain linkages (67,123). Notable exceptions are provided by USPL1 which is a SUMO-specific protease (230), USP18 which may be specific for the ubiquitin-like modifier, ISG15 (164) and CYLD which shows a marked preference for the open conformation presented by Lys63 and linear ubiquitin chains (27,123).…”

Section: A Chain Linkage Specificitymentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

375

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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“…Alternatively, cleavage products may have a very short half-life and therefore may be difficult to detect. Interestingly, a published work on the function of various USPs utilizes a USP1 protein lacking the first 20 amino acids, most likely to increase the stability of the recombinant protein (28). Notably, this first stretch of amino acids is identical in human, mouse, and rat USP1.…”

Section: Usp1 Interacts With Capns1mentioning

confidence: 99%

CAPNS1 Regulates USP1 Stability and Maintenance of Genome Integrity

Cataldo

Peche

Klaric

et al. 2013

Molecular and Cellular Biology

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cCalpains regulate a wide spectrum of biological functions, including migration, adhesion, apoptosis, secretion, and autophagy, through the modulating cleavage of specific substrates. Ubiquitous microcalpain (-calpain) and millicalpain (m-calpain) are heterodimers composed of catalytic subunits encoded, respectively, by CAPN1 and CAPN2 and a regulatory subunit encoded by CAPNS1. Here we show that calpain is required for the stability of the deubiquitinating enzyme USP1 in several cell lines. USP1 modulates DNA replication polymerase choice and repair by deubiquitinating PCNA. The ubiquitinated form of the USP1 substrate PCNA is stabilized in CAPNS1-depleted U2OS cells and mouse embryonic fibroblasts (MEFs), favoring polymeraseloading on chromatin and increased mutagenesis. USP1 degradation directed by the cell cycle regulator APC/C cdh1 , which marks USP1 for destruction in the G 1 phase, is upregulated in CAPNS1-depleted cells. USP1 stability can be rescued upon forced expression of calpain-activated Cdk5/p25, previously reported as a cdh1 repressor. These data suggest that calpain stabilizes USP1 by activating Cdk5, which in turn inhibits cdh1 and, consequently, USP1 degradation. Altogether these findings point to a connection between the calpain system and the ubiquitin pathway in the regulation of DNA damage response and place calpain at the interface between cell cycle modulation and DNA repair. Calpains regulate a wide spectrum of biological functions, including migration, adhesion, apoptosis, secretion, and autophagy through the modulated cleavage of specific substrates (reviewed in references 1-3). Ubiquitous microcalpain (-calpain) and millicalpain (m-calpain) are heterodimers composed of a catalytic subunit encoded, respectively, by CAPN1 and CAPN2 and a regulatory subunit encoded by CAPNS1. Both -calpain and mcalpain are negatively modulated by calpastatin. By a proteomic approach, we identified USP1 deubiquitinase as a CAPNS1-interacting protein. USP1 is a key modulator of DNA repair, partly through deubiquitination of its known targets FANCD2 (4, 5) and PCNA (6). Usp1 knockout (KO) mice have a severe phenotype and die soon after birth (7). Usp1 Ϫ/Ϫ cells are defective in FANCD2 focus formation and are hypersensitive to DNA damage (8). PCNA ubiquitination is higher in USP1-depleted cells than in control cells, thus leading to recruitment of error-prone, translesion DNA synthesis (TLS) polymerases and the consequent increase in mutation rate (6). USP1 promotes inhibitor of DNA binding (ID) protein stability and stem cell-like characteristics in osteosarcoma and is required for normal skeletogenesis (9). Interestingly, mice lacking CAPNS1 in cells of the osteoblast lineage are defective in bone development and remodeling in vivo (10).UV light irradiation activates hUSP1 autocleavage at glycines 670 and 671, inducing its subsequent proteasomal degradation (6). USP1 mutants with mutation in the catalytic cysteine 90 or in the autocleavage sites are more stable but can still be degraded in the cell (5), s...

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The Differential Modulation of USP Activity by Internal Regulatory Domains, Interactors and Eight Ubiquitin Chain Types

Cited by 191 publications

References 59 publications

Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

Deubiquitylases From Genes to Organism

CAPNS1 Regulates USP1 Stability and Maintenance of Genome Integrity

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