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Xing Wang Deng - One of the best experts on this subject based on the ideXlab platform.
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COP9 Signalosome discovery conservation activity and function
Journal of Integrative Plant Biology, 2020Co-Authors: Nanxun Qin, Xing Wang DengAbstract:The COP9 Signalosome (CSN) is a conserved protein complex, typically composed of eight subunits (designated as CSN1 to CSN8) in higher eukaryotes such as plants and animals, but of fewer subunits in some lower eukaryotes such as yeasts. The CSN complex is originally identified in plants from a genetic screen for mutants that mimic light-induced photomorphogenic development when grown in the dark. The CSN complex regulates the activity of cullin-RING ligase (CRL) families of E3 ubiquitin ligase complexes, and play critical roles in regulating gene expression, cell proliferation, and cell cycle. This review aims to summarize the discovery, composition, structure, and function of CSN in the regulation of plant development in response to external (light and temperature) and internal cues (phytohormones).
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plant COP9 Signalosome subunit 5 csn5
Plant Science, 2014Co-Authors: Dan Jin, Xing Wang Deng, Ning WeiAbstract:CSN5 is a subunit of the COP9 Signalosome (CSN) and carries the metallo-protease catalytic center for the complex. This highly conserved gene has been a subject of intense research in part because human Csn5 (Jab1) has been tightly linked to cancer. We briefly summarize recent research advances on the structure and mechanisms of the CSN in general, and then focus on the Arabidopsis CSN5 genes and their products, AtCSN5A and AtCSN5B. We also briefly discuss CSN6 genes, which are closely related share many similarities to CSN5. CSN5 and CSN6 genes are duplicated in mustard family of plants as well as in several plant species that have no phylogenetic correlation. Sequence homology comparison further suggests that at least some of the duplication events occurred independently. We review and analyze the phenotypic and expression differences of the two CSN5 genes in Arabidopsis, and suggest that they play overlapping as well as specialized roles in plant development. Arabidopsis CSN5 protein sequences are more similar to those of complex organisms such as humans than to yeasts and unicellular alga, suggesting that the structure and mechanism of Arabidopsis CSN5 likely resembles more to those of human than to yeast. We argue that possession of two different isoforms of CSN5s gives Arabidopsis a unique advantage as a genetic model of CSN5 to dissect the multifaceted functions and mechanistic versatilities of this important cellular regulator.
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regulation of cop1 nuclear localization by the COP9 Signalosome via direct interaction with csn1
Plant Journal, 2009Co-Authors: Xiping Wang, Xing Wang Deng, Raquel Piqueras, Kaiming Cao, Ning WeiAbstract:COP1 and COP9 Signalosome (CSN) are key regulators of plant light responses and development. Deficiency in either COP1 or CSN causes a constitutive photomorphogenic phenotype. Through coordinated actions of nuclear- and cytoplasmic-localization signals, COP1 can respond to light signals by differentially partitions between nuclear and cytoplasmic compartments. Previous genetic analysis in Arabidopsis indicated that the nuclear localization of COP1 requires CSN, an eight-subunit heteromeric complex. However the mechanism underlying the functional relationship between COP1 and CSN is unknown. We report here that COP1 weakly associates with CSN in vivo. Furthermore, we report on the direct interaction involving the coiled-coil domain of COP1 and the N-terminal domain of the CSN1 subunit. In onion epidermal cells, expression of CSN1 can stimulate nuclear localization of GUS-COP1, and the N-terminal domain of CSN1 is necessary and sufficient for this function. Moreover, CSN1-induced COP1 nuclear localization requires the nuclear-localization sequences of COP1, as well as its coiled-coil domain, which contains both the cytoplasmic localization sequences and the CSN1 interacting domain. We also provide genetic evidence that the CSN1 N-terminal domain is specifically required for COP1 nuclear localization in Arabidopsis hypocotyl cells. This study advances our understanding of COP1 localization, and the molecular interactions between COP1 and CSN.
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the COP9 Signalosome more than a protease
Trends in Biochemical Sciences, 2008Co-Authors: Ning Wei, Giovanna Serino, Xing Wang DengAbstract:The COP9 Signalosome (CSN) is a conserved protein complex that functions in the ubiquitin-proteasome pathway. After two decades of research, we now know that the CSN is a multi-subunit protease that regulates the activity of cullin-RING ligase (CRL) families of ubiquitin E3 complexes. The CSN is rapidly emerging as a key player in the DNA-damage response, cell-cycle control and gene expression. The independent functions of CSN5 (also known as JAB1) add to the complexity of the CSN machinery. Here, we provide an updated view of the structure, functions and regulation of this protein complex.
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COP9 Signalosome subunit 8 is essential for peripheral t cell homeostasis and antigen receptor induced entry into the cell cycle from quiescence
Nature Immunology, 2007Co-Authors: Suchithra Menon, Xing Wang Deng, Hongbo Chi, Huiyong Zhang, Richard A Flavell, Ning WeiAbstract:COP9 Signalosome subunit 8 is essential for peripheral T cell homeostasis and antigen receptor–induced entry into the cell cycle from quiescence
Ning Wei - One of the best experts on this subject based on the ideXlab platform.
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inositol hexakisphosphate ip6 generated by ip5k mediates cullin COP9 Signalosome interactions and crl function
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Paul C Scherer, Ning Wei, Yan Ding, Zhiqing Liu, Haibin Mao, James C Barrow, Ning Zheng, Solomon H Snyder, Feng RaoAbstract:The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) Signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL–CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC50 of 20 nM, acts as an intermolecular “glue,” increasing cullin–CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL–CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL–CSN system and are potential targets for cancer therapy in conjunction with MLN4924.
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COP9 Signalosome controls the degradation of cytosolic misfolded proteins and protects against cardiac proteotoxicity
Circulation Research, 2015Co-Authors: Hanming Zhang, Ning Wei, Jinbao Liu, Xuejun WangAbstract:Rationale:Impaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system, but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 Signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases, thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor cullin-RING ligases is known to regulate the degradation of cytosolic misfolded proteins. Objective:We sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy. Methods and Results:Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8hypo) mice were used. Myocardial neddylated forms of cullins were markedly increased, and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8 hypomorphism. Wh...
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plant COP9 Signalosome subunit 5 csn5
Plant Science, 2014Co-Authors: Dan Jin, Xing Wang Deng, Ning WeiAbstract:CSN5 is a subunit of the COP9 Signalosome (CSN) and carries the metallo-protease catalytic center for the complex. This highly conserved gene has been a subject of intense research in part because human Csn5 (Jab1) has been tightly linked to cancer. We briefly summarize recent research advances on the structure and mechanisms of the CSN in general, and then focus on the Arabidopsis CSN5 genes and their products, AtCSN5A and AtCSN5B. We also briefly discuss CSN6 genes, which are closely related share many similarities to CSN5. CSN5 and CSN6 genes are duplicated in mustard family of plants as well as in several plant species that have no phylogenetic correlation. Sequence homology comparison further suggests that at least some of the duplication events occurred independently. We review and analyze the phenotypic and expression differences of the two CSN5 genes in Arabidopsis, and suggest that they play overlapping as well as specialized roles in plant development. Arabidopsis CSN5 protein sequences are more similar to those of complex organisms such as humans than to yeasts and unicellular alga, suggesting that the structure and mechanism of Arabidopsis CSN5 likely resembles more to those of human than to yeast. We argue that possession of two different isoforms of CSN5s gives Arabidopsis a unique advantage as a genetic model of CSN5 to dissect the multifaceted functions and mechanistic versatilities of this important cellular regulator.
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the COP9 Signalosome is required for autophagy proteasome mediated proteolysis and cardiomyocyte survival in adult mice
Circulation-heart Failure, 2013Co-Authors: Hanna Osinska, Ning Wei, Jinbao Liu, Jeffrey Robbins, Xuejun WangAbstract:Background—The COP9 Signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 unique protein subunits (CSN1 through CSN8). We have recently discovered in perinatal mouse hearts that CSN regulates not only proteasome-mediated proteolysis but also macroautophagy. However, the physiological significance of CSN in a post-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts. Methods and Results—Csn8was conditionally ablated in the cardiomyocytes of adult mice (CSN8CKO) using a temporally controlled Cre-LoxP system. Loss of CSN8 accumulated the neddylated forms of cullins and noncullin proteins, increased ubiquitinated proteins, and stabilized a surrogate substrate of the proteasome in the heart. Autophagic flux was significantly decreased, whereas autophagosomes were markedly increased in CSN8CKO hearts, indicative of impaired autophagosome removal. Furthermore, we observed increased oxidized proteins, massi...
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COP9 Signalosome Regulates Autophagosome Maturation
Circulation, 2011Co-Authors: Mark J. Ranek, Ning Wei, Xuejun WangAbstract:Background—Autophagy is essential to intracellular homeostasis and is involved in the pathophysiology of a variety of diseases. Mechanisms regulating selective autophagy remain poorly understood. The COP9 Signalosome (CSN) is a conserved protein complex consisting of 8 subunits (CSN1 through CSN8), and is known to regulate the ubiquitin-proteasome system. However, it is unknown whether CSN plays a role in autophagy. Methods and Results—Marked increases in the LC3-II and p62 proteins were observed on Csn8 depletion in the cardiomyocytes of mouse hearts with cardiomyocyte-restricted knockout of the gene encoding CSN subunit 8 (CR-Csn8KO). The increases in autophagosomes were confirmed by probing with green fluorescent protein–LC3 and electron microscopy. Autophagic flux assessments revealed that defective autophagosome removal was the cause of autophagosome accumulation and occurred before a global ubiquitin-proteasome system impairment in Csn8-deficient hearts. Analyzing the prevalence of different stages ...
Daniel A Chamovitz - One of the best experts on this subject based on the ideXlab platform.
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role of COP9 Signalosome subunits in the environmental and hormonal balance of plant
Biomolecules, 2019Co-Authors: Daniel A Chamovitz, Amit Kumar SinghAbstract:The COP9 (Constitutive photomorphogenesis 9) Signalosome (CSN) is a highly conserved protein complex that influences several signaling and developmental processes. The COP9 Signalosome consists of eight subunits, among which two subunits, CSN5 and CSN6, contain an Mpr1/Pad1 N-terminal (MPN) domain and the remaining six subunits contain a proteasome, COP9 Signalosome, and initiation factor 3 (PCI) domain. In plants, each MPN subunit is encoded by two genes, which is not the case in other organisms. This review aims to provide in-depth knowledge of each COP9 Signalosome subunit, concentrating on genetic analysis of both partial and complete loss-of-function mutants. At the beginning of this review, the role of COP9 Signalosome in the hormonal signaling and defense is discussed, whereas later sections deal in detail with the available partial loss-of-function, hypomorphic mutants of each subunit. All available hypomorphic mutants are compared based on their growth response and deneddylation activity.
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the organization of a csn5 containing subcomplex of the COP9 Signalosome
Journal of Biological Chemistry, 2012Co-Authors: Giri Gowda Kotiguda, Giovanna Serino, Daniel A Chamovitz, Moshe Dessau, Dahlia Weinberg, Chiara Salvi, Joel A HirschAbstract:The COP9 Signalosome (CSN) is an evolutionarily conserved multi-protein complex that interfaces with the ubiquitin-proteasome pathway and plays critical developmental roles in both animals and plants. Although some subunits are present only in an ∼320-kDa complex-dependent form, other subunits are also detected in configurations distinct from the 8-subunit holocomplex. To date, the only known biochemical activity intrinsic to the complex, deneddylation of the Cullin subunits from Cullin-RING ubiquitin ligases, is assigned to CSN5. As an essential step to understanding the structure and assembly of a CSN5-containing subcomplex of the CSN, we reconstituted a CSN4-5-6-7 subcomplex. The core of the subcomplex is based on a stable heterotrimeric association of CSN7, CSN4, and CSN6, requiring coexpression in a bacterial reconstitution system. To this heterotrimer, we could then add CSN5 in vitro to reconstitute a quaternary complex. Using biochemical and biophysical methods, we identified pairwise and combinatorial interactions necessary for the formation of the CSN4-5-6-7 subcomplex. The subcomplex is stabilized by three types of interactions: MPN-MPN between CSN5 and CSN6, PCI-PCI between CSN4 and CSN7, and interactions mediated through the CSN6 C terminus with CSN4 and CSN7. CSN8 was also found to interact with the CSN4-6-7 core. These data provide a strong framework for further investigation of the organization and assembly of this pivotal regulatory complex.
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revisiting the COP9 Signalosome as a transcriptional regulator
EMBO Reports, 2009Co-Authors: Daniel A ChamovitzAbstract:The COP9 Signalosome (CSN) is a highly conserved protein complex that was originally described as a repressor of light-dependent growth and transcription in Arabidopsis. The most studied CSN function is the regulation of protein degradation, which occurs primarily through the removal of the ubiquitin-like modifier Nedd8 from cullin-based E3 ubiquitin ligases. This activity can regulate transcription-factor stability and, therefore, transcriptional activity. Recent data suggest that the CSN also regulates transcription on the chromatin by mechanisms that are not yet clearly understood. Furthermore, the CSN subunits CSN5 and CSN2 seem to act as transcriptional coactivators and corepressors, respectively. Here, I re-evaluate the mechanisms by which the CSN acts as a transcriptional regulator, and suggest that they could extend beyond the regulation of protein stability.
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the arabidopsis COP9 Signalosome subunit 7 is a model pci domain protein with subdomains involved in COP9 Signalosome assembly
The Plant Cell, 2008Co-Authors: Moshe Dessau, Daniel A Chamovitz, Yair Halimi, Tamir Erez, Orna Chomskyhecht, Joel A HirschAbstract:The COP9 Signalosome (CSN) is a multiprotein complex that was originally identified in Arabidopsis thaliana as a negative regulator of photomorphogenesis and subsequently shown to be a general eukaryotic regulator of developmental signaling. The CSN plays various roles, but it has been most often implicated in regulating protein degradation pathways. Six of eight CSN subunits bear a sequence motif called PCI. Here, we report studies of subunit 7 (CSN7) from Arabidopsis, which contains such a motif. Our in vitro and structural results, based on 1.5 A crystallographic data, enable a definition of a PCI domain, built from helical bundle and winged helix subdomains. Using functional binding assays, we demonstrate that the PCI domain (residues 1 to 169) interacts with two other PCI proteins, CSN8 and CSN1. CSN7 interactions with CSN8 use both PCI subdomains. Furthermore, we show that a C-terminal tail outside of this PCI domain is responsible for association with the non-PCI subunit, CSN6. In vivo studies of transgenic plants revealed that the overexpressed CSN7 PCI domain does not assemble into the CSN, nor can it complement a null mutation of CSN7. However, a CSN7 clone that contains the PCI domain plus part of the CSN6 binding domain can complement the null mutation in terms of seedling viability and photomorphogenesis. These transgenic plants, though, are defective in adult growth, suggesting that the CSN7 C-terminal tail plays additional functional roles. Together, the findings have implications for CSN assembly and function, highlighting necessary interactions between subunits.
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COP9 Signalosome subunits 4 and 5 regulate multiple pleiotropic pathways in drosophila melanogaster
Development, 2002Co-Authors: Efrat Oron, Daniel L Segal, Mattias Mannervik, Sigal Rencus, Orit Hararisteinberg, Shira Neumansilberberg, Daniel A ChamovitzAbstract:The COP9 Signalosome (CSN) is an essential eight-subunit repressor of light-regulated development in Arabidopsis. This complex has also been identified in animals, though its developmental role remains obscure. CSN subunits have been implicated in various cellular processes, suggesting a possible role for the CSN as an integrator of multiple signaling pathways. In order to elucidate the function of the CSN in animals, a Drosophila model system has previously been established. Gel-filtration analysis with antibodies against CSN subunits 4, 5 and 7 revealed that these proteins act as a complex in Drosophila that is similar in size to the plant and mammalian complexes. Null mutations in either one of two subunits, CSN4 or CSN5, are larval lethal. Successful embryogenesis appears to be a consequence of maternal contribution of the complex. Biochemical analysis indicates that the different subunits are found in both CSN-dependent and CSN-independent forms, and that these forms are differentially affected by the mutations. Phenotypic characterization of these two mutants indicates that they show both shared and unique phenotypes, which suggest specific roles for each subunit. Both mutants have defective oocyte and embryo patterning, and defects in response to DNA damage, while csn5 mutants develop melanotic tumors and csn4 mutants have phenotypes reminiscent of defects in ecdysone signaling.
Wolfgang Dubiel - One of the best experts on this subject based on the ideXlab platform.
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diversity of COP9 Signalosome structures and functional consequences
FEBS Letters, 2015Co-Authors: Dawadschargal Dubiel, Michael Naumann, Beate Rockel, Wolfgang DubielAbstract:The COP9 Signalosome (CSN) is a regulator of the ubiquitin (Ub) proteasome system (UPS). It interacts with hundreds of cullin-RING ubiquitin E3 ligases (CRLs) and regulates their activity by removing the Ub-like protein Nedd8 from cullins. In mammalian cells 7 different cullins exist which form CRLs with adaptor proteins and with a large number of substrate recognition subunits such as F-box and BTB proteins. This large variety of CRL-complexes is deneddylated by the CSN. The capacity of the CSN to interact with numerous types of CRL complexes can be explained by its structural diversity, which allows different CSN variants to interact with different binding partners and substrates and enables different subunit expression profiles. Diversity of CSN complexes presumably occurs by: (1) flexibility of CSN holo complex structure; (2) formation of CSN mini complexes and free CSN subunits and (3) generation of CSN variants via integration of CSN subunit isoforms. In this review we will discuss the structural diversity of the CSN complex and possible functional consequences.
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control of multicellular development by the physically interacting deneddylases den1 dena and COP9 Signalosome
PLOS Genetics, 2013Co-Authors: Martin Christmann, Wolfgang Dubiel, Xiaohua Huang, Özgür Bayram, Tilo Schmaler, Colin Gordon, Josua Schinke, Sina Stumpf, Gerhard H. BrausAbstract: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.
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COP9 Signalosome function in the ddr
FEBS Letters, 2011Co-Authors: Ronny Hanns, Wolfgang DubielAbstract:The COP9 Signalosome (CSN) is a platform for protein communication in eukaryotic cells. It has an intrinsic metalloprotease that removes the ubiquitin (Ub)-like protein Nedd8 from cullins. CSN-mediated deneddylation regulates culling-RING Ub ligases (CRLs) and controls ubiquitination of proteins involved in DNA damage response (DDR). CSN forms complexes with CRLs containing cullin 4 (CRL4s) which act on chromatin playing crucial roles in DNA repair, checkpoint control and chromatin remodeling. Furthermore, via associated kinases the CSN controls the stability of DDR effectors such as p53 and p27 and thereby the DDR outcome. DDR is a protection against cancer and deregulation of CSN function causes cancer making it an attractive pharmacological target. Here we review current knowledge on CSN function in DDR.
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consequences of COP9 Signalosome and 26s proteasome interaction
FEBS Journal, 2005Co-Authors: Xiaohua Huang, Michael Naumann, Dawadschargal Bechotschir, Bettina K J Hetfeld, Ulrike Seifert, Thilo Kahne, Petermichael Kloetzel, Wolfgang DubielAbstract:The COP9 Signalosome (CSN) occurs in all eukaryotic cells. It is a regulatory particle of the ubiquitin (Ub)/26S proteasome system. The eight subunits of the CSN possess sequence homologies with the polypeptides of the 26S proteasome lid complex and just like the lid, the CSN consists of six subunits with PCI (proteasome, COP9 Signalosome, initiation factor 3) domains and two components with MPN (Mpr-Pad1-N-terminal) domains. Here we show that the CSN directly interacts with the 26S proteasome and competes with the lid, which has consequences for the peptidase activity of the 26S proteasome in vitro. Flag-CSN2 was permanently expressed in mouse B8 fibroblasts and Flag pull-down experiments revealed the formation of an intact Flag-CSN complex, which is associated with the 26S proteasome. In addition, the Flag pull-downs also precipitated cullins indicating the existence of super-complexes consisting of the CSN, the 26S proteasome and cullin-based Ub ligases. Permanent expression of a chimerical subunit (Flag-CSN2-Rpn6) consisting of the N-terminal 343 amino acids of CSN2 and of the PCI domain of S9/Rpn6, the paralog of CSN2 in the lid complex, did not lead to the assembly of an intact complex showing that the PCI domain of CSN2 is important for complex formation. The consequence of permanent Flag-CSN2 overexpression was de-novo assembly of the CSN complex connected with an accelerated degradation of p53 and stabilization of c-Jun in B8 cells. The possible role of super-complexes composed of the CSN, the 26S proteasome and of Ub ligases in the regulation of protein stability is discussed.
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fission yeast COP9 Signalosome suppresses cullin activity through recruitment of the deubiquitylating enzyme ubp12p
Molecular Cell, 2003Co-Authors: Chunshui Zhou, Wolfgang Dubiel, Susan Wee, Edward Rhee, Michael Naumann, Dieter A WolfAbstract:The COP9/Signalosome (CSN) is known to remove the stimulatory NEDD8 modification from cullins. The activity of the fission yeast cullins Pcu1p and Pcu3p is dramatically stimulated when retrieved from csn mutants but inhibited by purified CSN. This inhibition is independent of cullin deneddylation but mediated by the CSN-associated deubiquitylating enzyme Ubp12p, which forms a complex with Pcu3p in a CSN-dependent manner. In ubp12 mutants, as in csn mutants, Pcu3p activity is stimulated. CSN is required for efficient targeting of Ubp12p to the nucleus, where both cullins reside. Finally, the CSN/Ubp12p pathway maintains the stability of the Pcu1p-associated substrate-specific adaptor protein Pop1p. We propose that CSN/Ubp12p-mediated deubiquitylation creates an environment for the safe de novo assembly of cullin complexes by counteracting the autocatalytic destruction of adaptor proteins.
Giovanna Serino - One of the best experts on this subject based on the ideXlab platform.
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the organization of a csn5 containing subcomplex of the COP9 Signalosome
Journal of Biological Chemistry, 2012Co-Authors: Giri Gowda Kotiguda, Giovanna Serino, Daniel A Chamovitz, Moshe Dessau, Dahlia Weinberg, Chiara Salvi, Joel A HirschAbstract:The COP9 Signalosome (CSN) is an evolutionarily conserved multi-protein complex that interfaces with the ubiquitin-proteasome pathway and plays critical developmental roles in both animals and plants. Although some subunits are present only in an ∼320-kDa complex-dependent form, other subunits are also detected in configurations distinct from the 8-subunit holocomplex. To date, the only known biochemical activity intrinsic to the complex, deneddylation of the Cullin subunits from Cullin-RING ubiquitin ligases, is assigned to CSN5. As an essential step to understanding the structure and assembly of a CSN5-containing subcomplex of the CSN, we reconstituted a CSN4-5-6-7 subcomplex. The core of the subcomplex is based on a stable heterotrimeric association of CSN7, CSN4, and CSN6, requiring coexpression in a bacterial reconstitution system. To this heterotrimer, we could then add CSN5 in vitro to reconstitute a quaternary complex. Using biochemical and biophysical methods, we identified pairwise and combinatorial interactions necessary for the formation of the CSN4-5-6-7 subcomplex. The subcomplex is stabilized by three types of interactions: MPN-MPN between CSN5 and CSN6, PCI-PCI between CSN4 and CSN7, and interactions mediated through the CSN6 C terminus with CSN4 and CSN7. CSN8 was also found to interact with the CSN4-6-7 core. These data provide a strong framework for further investigation of the organization and assembly of this pivotal regulatory complex.
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the COP9 Signalosome more than a protease
Trends in Biochemical Sciences, 2008Co-Authors: Ning Wei, Giovanna Serino, Xing Wang DengAbstract:The COP9 Signalosome (CSN) is a conserved protein complex that functions in the ubiquitin-proteasome pathway. After two decades of research, we now know that the CSN is a multi-subunit protease that regulates the activity of cullin-RING ligase (CRL) families of ubiquitin E3 complexes. The CSN is rapidly emerging as a key player in the DNA-damage response, cell-cycle control and gene expression. The independent functions of CSN5 (also known as JAB1) add to the complexity of the CSN machinery. Here, we provide an updated view of the structure, functions and regulation of this protein complex.
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the COP9 Signalosome regulating plant development through the control of proteolysis
Annual Review of Plant Biology, 2003Co-Authors: Giovanna Serino, Xing Wang DengAbstract:The COP9 Signalosome (CSN) is a multiprotein complex that was initially identified in plants as a repressor of photomorphogenesis. It is now known to play major roles in several other developmental pathways, from auxin response to flower development. Furthermore, the COP9 Signalosome shares homologies with the lid sibcomplex of the proteasome and is evolutionarily conserved from fission yeast to humans. It is important for the proper development of virtually all higher eukaryotes. In recent years, significant progress has been made in unraveling the molecular, cellular, and physiological mode of action of the COP9 Signalosome. This review discusses our current understanding of the COP9 Signalosome function with particular emphasis on its recently defined role in modulating a wide variety of cellular processes by regulating specific protein degradation events.
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multiple ubiquitin ligase mediated processes require COP9 Signalosome and axr1 function
The Plant Cell, 2002Co-Authors: Claus Schwechheimer, Giovanna Serino, Xing Wang DengAbstract:The COP9 Signalosome (CSN) is an evolutionarily conserved multiprotein complex that mediates the repression of photomorphogenesis in the dark in Arabidopsis through the degradation of transcription factors such as HY5 and HYH. CSN-mediated HY5 and HYH degradation also requires the activity of the putative E3 ubiquitin ligase (E3) component COP1 and the E2-conjugating enzyme variant COP10. Recently, it was shown that CSN also is required for auxin responses mediated by the SCF-type E3 SCF(TIR1). To determine whether Arabidopsis CSN is required for E3-mediated processes in a more general manner, we generated plants with reduced E3 function by suppressing AtRBX1, an essential core subunit of SCF-type E3s. We observed that AtRBX1 transgenic plants share multiple phenotypes with CSN reduced-function plants, such as morphological defects and reduced responses to auxin, jasmonic acid, and cold stress, suggesting that CSN is required for multiple AtRBX1-mediated processes. Furthermore, we observed that mutants with defects in AXR1, a protein that had been described only as a regulator of SCF(TIR1) function, also is required for other E3-mediated processes and for the COP1/COP10/CSN-mediated repression of photomorphogenesis in the dark. We conclude that CSN and AXR1 are of general importance for different pathways that are controlled by E3-mediated protein degradation.
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role of scf ubiquitin ligase and the COP9 Signalosome in the n gene mediated resistance response to tobacco mosaic virus
The Plant Cell, 2002Co-Authors: Yule Liu, Xing Wang Deng, Giovanna Serino, Michael Schiff, S P DineshkumarAbstract:The tobacco N gene confers resistance to Tobacco mosaic virus (TMV) and encodes a toll–interleukin-1 receptor/nucleotide binding/Leu-rich repeat class protein. Recent evidence indicates that the Nicotiana benthamiana Rar1 gene (NbRar1), which encodes a protein with a zinc finger motif called CHORD (Cys- and His-rich domain), is required for the function of N. To investigate the role of NbRar1 in plant defense, we identified its interaction partners. We show that the NbRar1 protein interacts with NbSGT1, a highly conserved component of the SCF (Skp1/Cullin/F-box protein)-type E3 ubiquitin ligase complex involved in protein degradation. In addition, we show that NbSGT1 interacts with NbSKP1. Suppression of NbSGT1 and NbSKP1 shows that these genes play an important role in the N-mediated resistance response to TMV. Both NbRar1 and NbSGT1 associate with the COP9 Signalosome, another multiprotein complex involved in protein degradation via the ubiquitin-proteasome pathway. Silencing of the NbCOP9 Signalosome also compromises N-mediated resistance to TMV. Our results reveal new roles for SCF and the COP9 Signalosome in plant defense signaling.