The WD40‐repeat protein CreC interacts with and stabilizes the deubiquitinating enzyme CreB <i>in vivo</i> in <i>Aspergillus nidulans</i>

Lockington, Robin; Kelly, Joseph F.

doi:10.1046/j.1365-2958.2002.02811.x

Cited by 70 publications

(59 citation statements)

References 45 publications

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“…Its function may be suggested from the studies in Aspergillus nidulans (20), where CreC protein of A. nidulans, an apparent orthologue of WDR20, is required for the stabilization of CreB, an orthologue of USP12. The Cre proteins are involved in transcriptional regulation under catabolite repression, where CreA protein, a transcription factor, was hypothesized to be a substrate of the DUB CreB.…”

Section: Discussionmentioning

confidence: 99%

WDR20 Regulates Activity of the USP12·UAF1 Deubiquitinating Enzyme Complex

Kee

Yang

Cohn

et al. 2010

Journal of Biological Chemistry

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The UAF1 (Usp1-associated factor 1) protein binds and stimulates three deubiquitinating enzymes: USP1, USP12, and USP46. Although the USP1⅐UAF1 complex is required for regulation of the Fanconi anemia (FA) DNA repair pathway, less is known about the USP12⅐UAF1 and the USP46⅐UAF1 complexes. To understand further the nature of the USP12 and USP46 complexes, we attempted to identify proteins that interact with the USP12 and USP46 deubiquitinating enzyme complexes. We identified WDR20, a WD40-repeat containing protein, as a common binding partner of UAF1, USP12, and USP46. Further analysis showed that WDR20 associates exclusively with USP12 and USP46, not with USP1. Furthermore, we demonstrate the purification of a ternary USP12⅐UAF1⅐WDR20 complex. Interestingly, and consistent with the binding assays, WDR20 stimulated the enzymatic activity of USP12⅐UAF1, but not of USP1⅐UAF1. Consistent with our previous report that USP12 and USP46 do not regulate the FA pathway, small interference RNA-mediated depletion of WDR20 protein did not affect the FA pathway or DNA damage responses. We provide a model in which WDR20 serves as a stimulatory subunit for preserving and regulating the activity of the subset of the UAF1⅐USP complexes.Balanced ubiquitination and deubiquitination regulates numerous cellular processes. Increasing reports suggest that deubiquitination of proteins, the reversal process of ubiquitination, is as an a important step as ubiquitination, for specific regulation of particular cellular pathways (1, 2). For instance, deubiquitinating enzymes (DUBs) 6 are critical regulators of the p53/mdm2 (3), NFB signaling (4, 5), and the Fanconi anemia (FA) DNA repair pathways (6), by directly removing the ubiquitin moieties from their substrates. Deubiquitination either rescues the proteins from proteosome-mediated degradation or alters the activities of the proteins. For instance, USP7⅐HAUSP regulates the dynamics of p53-dependent pathways by directly deubiquitinating p53 and Mdm2 (3). CYLD suppresses the NFB pathway by deubiquitinating Lys 63 -linked polyubiquitination of NEMO, a regulatory subunit for IB kinase and TRAF2-6 E3 ligases. USP1 deubiquitinates monoubiquitinated FANCD2, which is an important regulator of the FA pathway, a step required for the completion of this DNA repair pathway (6). Inactivation of the DUBs result in abnormal cellular phenotypes in various organism settings (7-10), further suggesting that deubiquitination is a critical step in a variety of biological processes.There are ϳ95 putative DUBs encoded by human cells, and they can be divided into five subfamilies (2, 11). Four families belong to cysteine proteases, including ubiquitin C-terminal hydrolases (Uchs), ubiquitin-specific proteases (USPs), otubain proteases (OTUs), and Josephine domain proteases (MJDs), with the fifth one being JAB1/MPN/Mov34 (JAMM) metalloproteases.Although the identities of target substrates and biological functions are critical questions for the majority of the DUBs, another important issue is the mechanism of ...

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Section: Discussionmentioning

confidence: 99%

WDR20 Regulates Activity of the USP12·UAF1 Deubiquitinating Enzyme Complex

Kee

Yang

Cohn

et al. 2010

Journal of Biological Chemistry

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“…181,182 The proposed model for CCR through CreA modification or stability involves the CreB deubiquitination enzyme complexing with the CreC protein to modify or stabilize CreA under carbon-repressing conditions. 183 An additional gene implicated in the mechanism of A. nidulans CCR is creD. Mutations in this gene suppress the creB15 and creC27 mutant phenotypes, showing derepression of facA and alcA genes.…”

Section: Aspergillus Nidulansmentioning

confidence: 99%

Carbon source regulation of antibiotic production

et al. 2010

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“…Furthermore, regulation of CreA is thought to occur via the removal of ubiquitin molecules from the protein that leads to active CreA, a process that may be mediated by the CreB-CreC deubiquitination (DUB) complex (Lockington and Kelly 2002). CreB is a ubiquitin-specific processing (UBP) family protease that functions downstream of CreC; the latter is a WD-40 domain protein required for CreB stabilization (Lockington and Kelly 2002). Deubiquitinating enzymes are cysteine proteases that target the activation domains of specific transcription factors.…”

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confidence: 99%

Diverse Regulation of the CreA Carbon Catabolite Repressor in Aspergillus nidulans

et al. 2016

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Carbon catabolite repression (CCR) is a process that selects the energetically most favorable carbon source in an environment. CCR represses the use of less favorable carbon sources when a better source is available. Glucose is the preferential carbon source for most microorganisms because it is rapidly metabolized, generating quick energy for growth. In the filamentous fungus Aspergillus nidulans, CCR is mediated by the transcription factor CreA, a C 2 H 2 finger domain DNA-binding protein. The aim of this work was to investigate the regulation of CreA and characterize its functionally distinct protein domains. CreA depends in part on de novo protein synthesis and is regulated in part by ubiquitination. CreC, the scaffold protein in the CreB-CreC deubiquitination (DUB) complex, is essential for CreA function and stability. Deletion of select protein domains in CreA resulted in persistent nuclear localization and target gene repression. A region in CreA conserved between Aspergillus spp. and Trichoderma reesei was identified as essential for growth on various carbon, nitrogen, and lipid sources. In addition, a role of CreA in amino acid transport and nitrogen assimilation was observed. Taken together, these results indicate previously unidentified functions of this important transcription factor. These novel functions serve as a basis for additional research in fungal carbon metabolism with the potential aim to improve fungal industrial applications.

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The WD40‐repeat protein CreC interacts with and stabilizes the deubiquitinating enzyme CreB in vivo in Aspergillus nidulans

Cited by 70 publications

References 45 publications

WDR20 Regulates Activity of the USP12·UAF1 Deubiquitinating Enzyme Complex

WDR20 Regulates Activity of the USP12·UAF1 Deubiquitinating Enzyme Complex

Carbon source regulation of antibiotic production

Diverse Regulation of the CreA Carbon Catabolite Repressor in Aspergillus nidulans

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