The WD40-repeat Proteins WDR-20 and WDR-48 Bind and Activate the Deubiquitinating Enzyme USP-46 to Promote the Abundance of the Glutamate Receptor GLR-1 in the Ventral Nerve Cord of Caenorhabditis elegans

Dahlberg, Caroline L.; Juo, Peter

doi:10.1074/jbc.m113.507541

Cited by 40 publications

(80 citation statements)

References 55 publications

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“…Nevertheless, we can offer some possibilities based on our current knowledge of the endogenous functions of USP1, USP12, and USP46. These three USPs have been implicated in the regulation of the stability of various proteins, including the glutamate receptor (GLR-1), the inhibitors of DNA binding (IDs), and the protein phosphatase PHLPP1 (34,(38)(39)(40). On the basis of these observations, it is tempting to speculate that recruitment of these UAF1-USP complexes to the HPV origin serves to regulate the stability of one or more components of the viral replisome.…”

Section: Discussionmentioning

confidence: 97%

“…The binding of UAF1 to USP1, USP12, or USP46 was previously shown to stimulate the deubiquitinase activity of these enzymes (24,25,34). In the case of USP1, this stimulation is thought to proceed through modulation of the enzyme active site, resulting in a higher catalytic efficiency (k cat ) but no substantial change in substrate-binding affinity (K m ) (32).…”

Section: Discussionmentioning

confidence: 99%

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E1-Mediated Recruitment of a UAF1-USP Deubiquitinase Complex Facilitates Human Papillomavirus DNA Replication

Lehoux

Gagnon

Archambault

2014

J Virol

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The human papillomavirus (HPV) E1 helicase promotes viral DNA replication through its DNA unwinding activity and association with host factors. The E1 proteins from anogenital HPV types interact with the cellular WD repeat-containing factor UAF1 (formerly known as p80). Specific amino acid substitutions in E1 that impair this interaction inhibit maintenance of the viral episome in immortalized keratinocytes and reduce viral DNA replication by up to 70% in transient assays. In this study, we determined by affinity purification of UAF1 that it interacts with three deubiquitinating enzymes in C33A cervical carcinoma cells: USP1, a nuclear protein, and the two cytoplasmic enzymes USP12 and USP46. Coimmunoprecipitation experiments indicated that E1 assembles into a ternary complex with UAF1 and any one of these three USPs. Moreover, expression of E1 leads to a redistribution of USP12 and USP46 from the cytoplasm to the nucleus. Chromatin immunoprecipitation studies further revealed that E1 recruits these threes USPs to the viral origin in association with UAF1. The function of USP1, USP12, and USP46 in viral DNA replication was investigated by overproduction of catalytically inactive versions of these enzymes in transient assays. All three dominant negative USPs reduced HPV31 DNA replication by up to 60%, an effect that was specific, as it was not observed in assays performed with a truncated E1 lacking the UAF1-binding domain or with bovine papillomavirus 1 E1, which does not bind UAF1. These results highlight the importance of the USP1, USP12, and USP46 deubiquitinating enzymes in anogenital HPV DNA replication. IMPORTANCEHuman papillomaviruses are small DNA tumor viruses that induce benign and malignant lesions of the skin and mucosa. HPV types that infect the anogenital tract are the etiological agents of cervical cancer, the majority of anal cancers, and a growing proportion of head-and-neck cancers. Replication of the HPV genome requires the viral protein E1, a DNA helicase that also interacts with host factors to promote viral DNA synthesis. We previously reported that the E1 helicase from anogenital HPV types associates with the WD40 repeat-containing protein UAF1. Here, we show that UAF1 bridges the interaction of E1 with three deubiquitinating enzymes, USP1, USP12, and USP46. We further show that these deubiquitinases are recruited by E1/UAF1 to the viral origin of DNA replication and that overexpression of catalytically inactive versions of these enzymes reduces viral DNA replication. These results highlight the need for an E1-associated deubiquitinase activity in anogenital HPV genome replication.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

E1-Mediated Recruitment of a UAF1-USP Deubiquitinase Complex Facilitates Human Papillomavirus DNA Replication

Lehoux

Gagnon

Archambault

2014

J Virol

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“…USP1, the founding member of this USP subfamily, plays an essential role in the Fanconi anemia (FA) DNA repair pathways by removing mono-ubiquitin from FANCD2 and PCNA (Huang et al, 2006; Kim and D’Andrea, 2012; Moldovan and D’Andrea, 2009; Nijman et al, 2005a). USP12 and USP46, on the other hand, are two closely related DUBs responsible for deubiquitinating and stabilizing a variety of protein substrates in cell signaling (Burska et al, 2013; Dahlberg and Juo, 2014; Gangula and Maddika, 2013; Joo et al, 2011; Li et al, 2013; McClurg et al, 2014; Moretti et al, 2012). USP12, in particular, is implicated in prostate cancer as a co-activator of the androgen receptor and is overexpressed in colorectal carcinoma driven by a focally amplified super-enhancer (Burska et al, 2013; Zhang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Recent affinity-based analyses have identified an evolutionarily conserved WD40-repeat containing protein, UAF1 (USP1-associated factor 1), which can directly interact with all three USPs (Cohn et al, 2007; Sowa et al, 2009). Although in isolation these three USP enzymes are mostly inactive, their isopeptidase activities are strongly enhanced upon binding to UAF1 (Cohn et al, 2009; Dahlberg and Juo, 2014; Gangula and Maddika, 2013). Interestingly, USP12 and USP46, but not USP1, can be independently activated by another WD40-repeat containing protein, WDR20 (Burska et al, 2013; Dahlberg and Juo, 2014; Kee et al, 2010; McClurg et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Although in isolation these three USP enzymes are mostly inactive, their isopeptidase activities are strongly enhanced upon binding to UAF1 (Cohn et al, 2009; Dahlberg and Juo, 2014; Gangula and Maddika, 2013). Interestingly, USP12 and USP46, but not USP1, can be independently activated by another WD40-repeat containing protein, WDR20 (Burska et al, 2013; Dahlberg and Juo, 2014; Kee et al, 2010; McClurg et al, 2014). Together, UAF1 and WDR20 are able to synergistically stimulate the enzymatic activities of USP12 and USP46 to a peak level.…”

Section: Introductionmentioning

confidence: 99%

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Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20

Lim

Kim

et al. 2016

Molecular Cell

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SUMMARY Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two β-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far away from its catalytic center. Without increasing substrate affinity of USP12, the two β-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach to a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.

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The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases

2022

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Despite annual increases in the incidence and prevalence of neurodegenerative diseases, there is a lack of effective treatment strategies. An increasing number of E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs) have been observed to participate in the pathogenesis mechanisms of neurodegenerative diseases, on the basis of which we conducted a systematic literature review of the studies. This review will help to explore promising therapeutic targets from highly dynamic ubiquitination modification processes.

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The WD40-repeat Proteins WDR-20 and WDR-48 Bind and Activate the Deubiquitinating Enzyme USP-46 to Promote the Abundance of the Glutamate Receptor GLR-1 in the Ventral Nerve Cord of Caenorhabditis elegans

Cited by 40 publications

References 55 publications

E1-Mediated Recruitment of a UAF1-USP Deubiquitinase Complex Facilitates Human Papillomavirus DNA Replication

E1-Mediated Recruitment of a UAF1-USP Deubiquitinase Complex Facilitates Human Papillomavirus DNA Replication

Allosteric Activation of Ubiquitin-Specific Proteases by β-Propeller Proteins UAF1 and WDR20

The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases

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