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Function of COP9 Signalosome in Regulation of Mouse Oocytes Meiosis by Regulating MPF Activity and Securing Degradation  [PDF]
Eunju Kim, Se-Jin Yoon, Eun-Young Kim, Yunna Kim, Hyun-Seo Lee, Kyeoung-Hwa Kim, Kyung-Ah Lee
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025870
Abstract: The COP9 (constitutive photomorphogenic) signalosome (CSN), composed of eight subunits, is a highly conserved protein complex that regulates processes such as cell cycle progression and kinase signalling. Previously, we found the expression of the COP9 constitutive photomorphogenic homolog subunit 3 (CSN3) and subunit 5 (CSN5) changes as oocytes mature for the first time, and there is no report regarding roles of COP9 in the mammalian oocytes. Therefore, in the present study, we examined the effects of RNA interference (RNAi)-mediated transient knockdown of each subunit on the meiotic cell cycle in mice oocytes. Following knockdown of either CSN3 or CSN5, oocytes failed to complete meiosis I. These arrested oocytes exhibited a disrupted meiotic spindle and misarranged chromosomes. Moreover, down-regulation of each subunit disrupted the activity of maturation-promoting factor (MPF) and concurrently reduced degradation of the anaphase-promoting complex/cyclosome (APC/C) substrates Cyclin B1 and Securin. Our data suggest that the CSN3 and CSN5 are involved in oocyte meiosis by regulating degradation of Cyclin B1 and Securin via APC/C.
Conservation of the COP9/signalosome in budding yeast
Susan Wee, Bettina Hetfeld, Wolfgang Dubiel, Dieter A Wolf
BMC Genetics , 2002, DOI: 10.1186/1471-2156-3-15
Abstract: We show that disruption of four budding yeast genes, PCI8 and three previously uncharacterized ORFs, which encode proteins interacting with Rrr1p/Csn5p, each results in the accumulation of the cullin Cdc53p exclusively in the Rub1p-modified state. This phenotype, which resembles that of fission yeast csn mutants, is due to a biochemical defect in deneddylation that is complemented by wild-type cell lysate and by purified human CSN in vitro. Although three of the four genes encode proteins with PCI domains conserved in metazoan CSN proteins, their disruption does not confer the DNA damage sensitivity described in some fission yeast csn mutants.Our studies present unexpected evidence for the conservation of a functional homologue of the metazoan CSN, which mediates control of cullin neddylation in budding yeast.The COP9/signalosome (CSN) was first identified in Arabidopsis thaliana as an eight subunit complex involved in the suppression of light-dependent development [1]. Subsequent studies have led to the identification of similar complexes in other plant species, Drosophila melanogaster, human cells, and fission yeast [2-7], thus indicating a high degree of structural conservation during evolution. Cloning of CSN subunits revealed their structural similarities to the eight subunits of the lid complex of the 26S proteasome [3,8-10]. The similarity was most pronounced within the so-called MPN domains of CSN5 and 6 and the PCI domains of the remaining subunits [11].CSN has been implicated in multiple biological processes, many involving ubiquitin-mediated proteolysis (reviewed in [12,13]). For example, CSN is required for degradation of the plant transcription factor HY5 by the putative COP1 ubiquitin ligase [14]. In addition, CSN is involved in auxin-induced turn-over of the transcriptional repressor AUX/IAA [15]. This process is mediated by an ubiquitin ligase [15] related to SCF complexes first identified in budding yeast [16,17]. All SCF complexes share the core su
Dual Regulation of Dendritic Morphogenesis in Drosophila by the COP9 Signalosome  [PDF]
Inna Djagaeva,Sergey Doronkin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007577
Abstract: Altered dendritic arborization contributes to numerous physiological processes including synaptic plasticity, behavior, learning and memory, and is one of the most consistent neuropathologic conditions found in a number of mental retardation disorders, schizophrenia, and neurodegenerative disease. COP9 signalosome (CSN), an evolutionarily conserved regulator of the Cullin-based ubiquitin ligases that act in the proteasome pathway, has been found associated with diverse debilitating syndromes, suggesting that CSN may be involved in regulation of dendritic arborization. However, the mechanism of this control, if it exists, is unknown. To address whether the CSN pathway plays a role in dendrites, we used a simple and genetically tractable model, Drosophila larval peripheral nervous system. Our model study identified the COP9 signalosome as the key and multilayer regulator of dendritic arborization. CSN is responsible for shaping the entire dendritic tree through both stimulating and then repressing dendritic branching. We identified that CSN exerts its dualistic function via control of different Cullins. In particular, CSN stimulates dendritic branching through Cullin1, and inhibits it via control of Cullin3 function. We also identified that Cullin1 acts in neurons with the substrate-specific F-box protein Slimb to target the Cubitus interruptus protein for degradation.
The CSN/COP9 Signalosome Regulates Synaptonemal Complex Assembly during Meiotic Prophase I of Caenorhabditis elegans  [PDF]
Heather Brockway,Nathan Balukoff,Martha Dean,Benjamin Alleva,Sarit Smolikove
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004757
Abstract: The synaptonemal complex (SC) is a conserved protein structure that holds homologous chromosome pairs together throughout much of meiotic prophase I. It is essential for the formation of crossovers, which are required for the proper segregation of chromosomes into gametes. The assembly of the SC is likely to be regulated by post-translational modifications. The CSN/COP9 signalosome has been shown to act in many pathways, mainly via the ubiquitin degradation/proteasome pathway. Here we examine the role of the CSN/COP9 signalosome in SC assembly in the model organism C. elegans. Our work shows that mutants in three subunits of the CSN/COP9 signalosome fail to properly assemble the SC. In these mutants, SC proteins aggregate, leading to a decrease in proper pairing between homologous chromosomes. The reduction in homolog pairing also results in an accumulation of recombination intermediates and defects in repair of meiotic DSBs to form the designated crossovers. The effect of the CSN/COP9 signalosome mutants on synapsis and crossover formation is due to increased neddylation, as reducing neddylation in these mutants can partially suppress their phenotypes. We also find a marked increase in apoptosis in csn mutants that specifically eliminates nuclei with aggregated SC proteins. csn mutants exhibit defects in germline proliferation, and an almost complete pachytene arrest due to an inability to activate the MAPK pathway. The work described here supports a previously unknown role for the CSN/COP9 signalosome in chromosome behavior during meiotic prophase I.
Control of Multicellular Development by the Physically Interacting Deneddylases DEN1/DenA and COP9 Signalosome  [PDF]
Martin Christmann equal contributor,Tilo Schmaler equal contributor,Colin Gordon,Xiaohua Huang,?zgür Bayram,Josua Schinke,Sina Stumpf,Wolfgang Dubiel ,Gerhard H. Braus
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003275
Abstract: Deneddylases remove the ubiquitin-like protein Nedd8 from modified proteins. An increased deneddylase activity has been associated with various human cancers. In contrast, we show here that a mutant strain of the model fungus Aspergillus nidulans deficient in two deneddylases is viable but can only grow as a filament and is highly impaired for multicellular development. The DEN1/DenA and the COP9 signalosome (CSN) deneddylases physically interact in A. nidulans as well as in human cells, and CSN targets DEN1/DenA for protein degradation. Fungal development responds to light and requires both deneddylases for an appropriate light reaction. In contrast to CSN, which is necessary for sexual development, DEN1/DenA is required for asexual development. The CSN-DEN1/DenA interaction that affects DEN1/DenA protein levels presumably balances cellular deneddylase activity. A deneddylase disequilibrium impairs multicellular development and suggests that control of deneddylase activity is important for multicellular development.
Neurospora COP9 Signalosome Integrity Plays Major Roles for Hyphal Growth, Conidial Development, and Circadian Function  [PDF]
Zhipeng Zhou,Ying Wang,Gaihong Cai,Qun He
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002712
Abstract: The COP9 signalosome (CSN) is a highly conserved multifunctional complex that has two major biochemical roles: cleaving NEDD8 from cullin proteins and maintaining the stability of CRL components. We used mutation analysis to confirm that the JAMM domain of the CSN-5 subunit is responsible for NEDD8 cleavage from cullin proteins in Neurospora crassa. Point mutations of key residues in the metal-binding motif (EXnHXHX10D) of the CSN-5 JAMM domain disrupted CSN deneddylation activity without interfering with assembly of the CSN complex or interactions between CSN and cullin proteins. Surprisingly, CSN-5 with a mutated JAMM domain partially rescued the phenotypic defects observed in a csn-5 mutant. We found that, even without its deneddylation activity, the CSN can partially maintain the stability of the SCFFWD-1 complex and partially restore the degradation of the circadian clock protein FREQUENCY (FRQ) in vivo. Furthermore, we showed that CSN containing mutant CSN-5 efficiently prevents degradation of the substrate receptors of CRLs. Finally, we found that deletion of the CAND1 ortholog in N. crassa had little effect on the conidiation circadian rhythm. Our results suggest that CSN integrity plays major roles in hyphal growth, conidial development, and circadian function in N. crassa.
The Minimal Deneddylase Core of the COP9 Signalosome Excludes the Csn6 MPN? Domain  [PDF]
Elah Pick, Amnon Golan, Jacob Z. Zimbler, Liquan Guo, Yehonatan Sharaby, Tomohiko Tsuge, Kay Hofmann, Ning Wei
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043980
Abstract: The COP9 signalosome (CSN) is a eukaryotic protein complex, which regulates a wide range of biological processes mainly through modulating the cullin ubiquitin E3 ligases in the ubiquitin-proteasome pathway. The CSN possesses a highly conserved deneddylase activity that centers at the JAMM motif of the Csn5 subunit but requires other subunits in a complex assembly. The classic CSN is composed of 8 subunits (Csn1–8), yet in several Ascomycota, the complex is smaller and lacks orthologs for a few CSN subunits, but nevertheless contains a conserved Csn5. This feature makes yeast a powerful model to determine the minimal assemblage required for deneddylation activity. Here we report, that Csi1, a diverged S. cerevisiae CSN subunit, displays significant homology with the carboxyl terminal domain of the canonical Csn6, but lacks the amino terminal MPN- domain. Through the comparative and experimental analyses of the budding yeast and the mammalian CSNs, we demonstrate that the MPN? domain of the canonical mouse Csn6 is not part of the CSN deneddylase core. We also show that the carboxyl domain of Csn6 has an indispensable role in maintaining the integrity of the CSN complex. The CSN complex assembled with the carboxyl fragment of Csn6, despite its lack of an MPN? domain, is fully active in deneddylation of cullins. We propose that the budding yeast Csi1 is a functional equivalent of the canonical Csn6, and thus the composition of the CSN across phyla is more conserved than hitherto appreciated.
The COP9 Signalosome Converts Temporal Hormone Signaling to Spatial Restriction on Neural Competence  [PDF]
Yi-Chun Huang,Yu-Nung Lu,June-Tai Wu,Cheng-Ting Chien ,Haiwei Pi
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004760
Abstract: During development, neural competence is conferred and maintained by integrating spatial and temporal regulations. The Drosophila sensory bristles that detect mechanical and chemical stimulations are arranged in stereotypical positions. The anterior wing margin (AWM) is arrayed with neuron-innervated sensory bristles, while posterior wing margin (PWM) bristles are non-innervated. We found that the COP9 signalosome (CSN) suppresses the neural competence of non-innervated bristles at the PWM. In CSN mutants, PWM bristles are transformed into neuron-innervated, which is attributed to sustained expression of the neural-determining factor Senseless (Sens). The CSN suppresses Sens through repression of the ecdysone signaling target gene broad (br) that encodes the BR-Z1 transcription factor to activate sens expression. Strikingly, CSN suppression of BR-Z1 is initiated at the prepupa-to-pupa transition, leading to Sens downregulation, and termination of the neural competence of PWM bristles. The role of ecdysone signaling to repress br after the prepupa-to-pupa transition is distinct from its conventional role in activation, and requires CSN deneddylating activity and multiple cullins, the major substrates of deneddylation. Several CSN subunits physically associate with ecdysone receptors to represses br at the transcriptional level. We propose a model in which nuclear hormone receptors cooperate with the deneddylation machinery to temporally shutdown downstream target gene expression, conferring a spatial restriction on neural competence at the PWM.
Downregulation of COP9 signalosome subunits differentially affects the CSN complex and target protein stability
Andreas Peth, Christoph Berndt, Wolfgang Henke, Wolfgang Dubiel
BMC Biochemistry , 2007, DOI: 10.1186/1471-2091-8-27
Abstract: Permanent knockdowns of CSN1 and CSN3 led to a reduction of the subunits to approximately 40%, which is accompanied by a proportional decrease of the CSN holocomplex. In contrast, downregulation of CSN5 in HeLa cells reduced the CSN5 protein below 20% without significant effects on the remaining complex. The CRL component Rbx1 was characterized by accelerated proteolysis in siCSN1 and siCSN3 and also in siCSN5 cells, however, with lesser extent. Immunoprecipitated CSN complex from siCSN5 cells was less effective in phosphorylating c-Jun and p27. Accelerated degradation of c-Jun in siCSN5 cells was rescued by overexpression of CSN5 as well as of the deneddylation mutant CSN5D151N. Overexpression of CSN5 cannot rescue c-Jun destabilization in siCSN1.There exists a coordinated downregulation of CSN subunits in the CSN1 and CSN3 knockdowns. The underlying regulatory mechanisms are obscure. CSN5 seems to possess a specific status in HeLa cells. Its reduction is not connected with coordinated downregulation of other subunits. CSN knockdowns confirm that the stabilization of the CRL component Rbx1 is a major CSN function. In addition, downregulation of CSN subunits influences the stability of important cellular regulators such as c-Jun and p27.The COP9 signalosome (CSN) is a conserved protein complex, which controls eukaryotic protein degradation via the ubiquitin (Ub) proteasome system (UPS) [1,2]. In mammals the core complex consists of 8 subunits (CSN1 to CSN8) [3], the exact function of which is not exactly known. CSN5 exhibits a MPN+/JAMM domain [4,5] responsible for metalloprotease activity. As a complex-bound protein CSN5 removes NEDD8, an ubiquitin-like protein, from cullins. This cleavage of an isopeptide bond called deneddylation controls the ubiquitination by cullin-RING Ub ligases (CRLs), a large family of multisubunit E3s [6,7]. Cullin proteins (Cul1 to Cul7) are components of CRLs functioning as scaffolds of the Ub ligase complexes. Cullin neddylation and den
Prediction of a common structural scaffold for proteasome lid, COP9-signalosome and eIF3 complexes
Hartmut Scheel, Kay Hofmann
BMC Bioinformatics , 2005, DOI: 10.1186/1471-2105-6-71
Abstract: During an exhaustive bioinformatical analysis of proteasome components, we detected multiple instances of tetratrico-peptide repeats (TPR) in the N-terminal region of most PCI proteins, suggesting that their homology is not restricted to the PCI domain. We also detected a previously unrecognized PCI domain in the eIF3 component eIF3k, a protein whose 3D-structure has been determined recently. By using profile-guided alignment techniques, we show that the structural elements found in eIF3k are most likely conserved in all PCI proteins, resulting in a structural model for the canonical PCI domain.Our model predicts that the homology domain PCI is not a true domain in the structural sense but rather consists of two subdomains: a C-terminal 'winged helix' domain with a key role in PCI:PCI interaction, preceded by a helical repeat region. The TPR-like repeats detected in the N-terminal region of PCI proteins most likely form an uninterrupted extension of the repeats found within the PCI domain boundaries. This model allows an interpretation of several puzzling experimental results.In eukaryotic organisms, there exist at least three distinct multi-protein assemblies that are jointly referred to as 'PCI complexes' [1] and have a similar subunit architecture despite their fundamentally different function: i) the proteasome lid, a subcomplex of the 19S proteasome regulator and the 26S proteasome, ii) the COP9 signalosome or CSN complex, and iii) the eukaryotic translation initiation factor eIF3. As a common feature, these complexes are composed of multiple subunits harbouring the PCI domain, named after the three participating complexes [2], sometimes also referred to as the PINT domain [3]. Other subunits of these complexes are characterized by a second shared homology domain called MPN (Mpr1-Pad1 N-terminal) [2,3].Among these complexes, the proteasome lid and the CSN share a particular degree of analogy. Both complexes consist of eight core subunits, six of them of the PCI
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