Requirement of Cul3 for Axonal Arborization and Dendritic Elaboration in<i>Drosophila</i>Mushroom Body Neurons

Zhu, Sijun; Perez, Rosanne; Pan, Marc; Lee, Tzumin

doi:10.1523/jneurosci.0149-05.2005

Cited by 41 publications

(27 citation statements)

References 51 publications

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“…1A, bottom panel). Neddylation of Cul3 occurs at a conserved C-terminal lysine residue (Lys 712 in human Cul3), and the biological importance of Nedd8 modification has been demonstrated for the Cul3 homologs in Drosophila melanogaster and Caenorhabditis elegans (36,46).…”

Section: Resultsmentioning

confidence: 99%

CAND1-Mediated Substrate Adaptor Recycling Is Required for Efficient Repression of Nrf2 by Keap1

Hannink

2006

Molecular and Cellular Biology

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The bZIP transcription factor Nrf2 controls a genetic program that protects cells from oxidative damage and maintains cellular redox homeostasis. Keap1, a BTB-Kelch protein, is the major upstream regulator of Nrf2. Keap1 functions as a substrate adaptor protein for a Cul3-dependent E3 ubiquitin ligase complex to repress steady-state levels of Nrf2 and Nrf2-dependent transcription. Cullin-dependent ubiquitin ligase complexes have been proposed to undergo dynamic cycles of assembly and disassembly that enable substrate adaptor exchange or recycling. In this report, we have characterized the importance of substrate adaptor recycling for regulation of Keap1-mediated repression of Nrf2. Association of Keap1 with Cul3 was decreased by ectopic expression of CAND1 and was increased by small interfering RNA (siRNA)-mediated knockdown of CAND1. However, both ectopic overexpression and siRNA-mediated knockdown of CAND1 decreased the ability of Keap1 to target Nrf2 for ubiquitin-dependent degradation, resulting in stabilization of Nrf2 and activation of Nrf2-dependent gene expression. Neddylation of Cul3 on Lys 712 is required for Keap1-dependent ubiquitination of Nrf2 in vivo. However, the K712R mutant Cul3 molecule, which is not neddylated, can still assemble with Keap1 into a functional ubiquitin ligase complex in vitro. These results provide support for a model in which substrate adaptor recycling is required for efficient substrate ubiquitination by cullin-dependent E3 ubiquitin ligase complexes.

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Section: Resultsmentioning

confidence: 99%

CAND1-Mediated Substrate Adaptor Recycling Is Required for Efficient Repression of Nrf2 by Keap1

Hannink

2006

Molecular and Cellular Biology

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“…26 APPL overexpression has been shown to induce post-developmental neurite arborization. 36 Similarly, Zhu et al 37 showed the cell-autonomous involvement of Drosophila Cul3 in axonal arborization and dendritic elaboration of mushroom body neurons. The neddylation of cullins is important for their proper functioning, so that the APPL overexpression phenotypes of these reports may be directly related to reduced neddylation.…”

Section: Discussionmentioning

confidence: 96%

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

Kim

et al. 2006

Cell Death Differ

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b-Amyloid precursor protein binding protein 1 (APP-BP1) was previously identified based on its binding to the carboxyl terminal of b-amyloid precursor protein. In this report, we have discovered that a mutation of dAPP-BP1 (Drosophila ortholog of APP-BP1) hinders tissue development, causes apoptosis in imaginal disc cells, and blocks the NEDD8 conjugation pathway. We show that dAPP-BP1 specifically binds the intracellular domain of APP-like protein (APPL). The dAPP-BP1 mutation partially suppresses the abnormal macrochaete phenotype of Appl d , while overexpression of dAPP-BP1 causes abnormal macrochaetes. When APPL is overexpressed, the normal bristle pattern in the fly thorax is disturbed and apoptosis is induced in wing imaginal discs. APPL overexpression phenotypes are enhanced by reducing the level of dAPP-BP1. APPL overexpression is shown to inhibit the NEDD8 conjugation pathway. APPL-induced apoptosis is rescued by overexpression of dAPP-BP1. Our data suggest that APPL and dAPP-BP1 interact antagonistically during Drosophila development.

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“…Nedd8 has been shown to enhance the ability of the ubiquitinconjugating enzyme Cdc34 to form a ubiquitin chain in a Cul1-dependent manner (Wu et al, 2000(Wu et al, , 2002. Nedd8 is also required in vivo for normal Cul3 function in Drosophila (Ou et al, 2002;Zhu et al, 2005), for early embryonic development in mice (Tateishi et al, 2001), and for the viability of Caenorhabditis elegans larvae (Kurz et al, 2002). Furthermore, the addition of the CSN complex to promote Cul1 deneddylation reduces the amount of ubiquitinated substrates in vitro, suggesting that Cul1 activity is inhibited when the Nedd8 linkage is removed (Zhou et al, 2003).…”

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confidence: 99%

The Cullin3 Ubiquitin Ligase Functions as a Nedd8-bound Heterodimer

Wimuttisuk

Singer

2007

MBoC

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Cullins are members of a family of scaffold proteins that assemble multisubunit ubiquitin ligase complexes to confer substrate specificity for the ubiquitination pathway. Cullin3 (Cul3) forms a catalytically inactive BTB-Cul3-Rbx1 (BCR) ubiquitin ligase, which becomes functional upon covalent attachment of the ubiquitin homologue neural-precursor-cellexpressed and developmentally down regulated 8 (Nedd8) near the C terminus of Cul3. Current models suggest that Nedd8 activates cullin complexes by providing a recognition site for a ubiquitin-conjugating enzyme. Based on the following evidence, we propose that Nedd8 activates the BCR ubiquitin ligase by mediating the dimerization of Cul3. First, Cul3 is found as a neddylated heterodimer bound to a BTB domain-containing protein in vivo. Second, the formation of a Cul3 heterodimer is mediated by a Nedd8 molecule, which covalently attaches itself to one Cul3 molecule and binds to the winged-helix B domain at the C terminus of the second Cul3 molecule. Third, complementation experiments revealed that coexpression of two distinct nonfunctional Cul3 mutants can rescue the ubiquitin ligase function of the BCR complex. Likewise, a substrate of the BCR complex binds heterodimeric Cul3, suggesting that the Cul3 complex is active as a dimer. These findings not only provide insight into the architecture of the active BCR complex but also suggest assembly as a regulatory mechanism for activation of all cullin-based ubiquitin ligases. INTRODUCTIONThe conjugation of ubiquitin to a lysine residue of a target protein serves as a signaling mechanism in many biological processes, such as protein trafficking, DNA repair, protein-protein interactions, and proteolysis (Hershko and Ciechanover, 1998;Pines and Lindon, 2005). These ubiquitin linkages are formed by a series of enzymes designated as ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3) (Ciechanover et al., 1980). A catalytically active ubiquitin ligase directly transfers ubiquitin molecules to the selected protein substrate, where a noncatalytic ubiquitin ligase shuttles the recruited substrate to a ubiquitin-conjugating enzyme (Glickman and Cienchanover, 2002). This latter group of E3 ligases includes cullin-based ubiquitin ligases, in which the cullin acts as a scaffold for the assembly of a multisubunit ubiquitin ligase complex that contains a RINGbox protein and a cullin-specific substrate adaptor protein (Ohta et al., 1999;Petroski and Deshaies, 2005). Cullin3 (Cul3) forms a complex called the BTB-Cul3-Rbx1 (BCR) ubiquitin ligase, which controls the degradation of several proteins, including cyclin E, the meiotic spindle-formation factor Mei-1, the transcription factor Nrf2, the Ci/Gli transcription factor, and the Dishevelled protein in the Wnt-␤-catenin pathway (Singer et al., 1999;Pintard et al., 2003b;Zhang et al., 2004Zhang et al., , 2006Angers et al., 2006). The BCR complex acquires its substrate specificity through a BTB domaincontaining protein bound at the N terminus ...

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Requirement of Cul3 for Axonal Arborization and Dendritic Elaboration inDrosophilaMushroom Body Neurons

Cited by 41 publications

References 51 publications

CAND1-Mediated Substrate Adaptor Recycling Is Required for Efficient Repression of Nrf2 by Keap1

CAND1-Mediated Substrate Adaptor Recycling Is Required for Efficient Repression of Nrf2 by Keap1

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

The Cullin3 Ubiquitin Ligase Functions as a Nedd8-bound Heterodimer

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