Hemizygosity for the COP9 signalosome subunit gene,SGN3, in the Smith-Magenis syndrome

Elsea, Sarah H.; Mykytyn, Kirk; Ferrell, Katherine; Coulter, Kathryn L.; Das, Parimal; Dubiel, Wolfgang; Patel, Pragna I.; Metherall, James E.

doi:10.1002/(sici)1096-8628(19991203)87:4<342::aid-ajmg12>3.0.co;2-a

Cited by 24 publications

(7 citation statements)

References 25 publications

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“…Because mental disorders are often accompanied by a misbalanced dendritic appearance [3], [56], the role of CSN in keeping the proper degree of dendritic arborization in the human brain could be central. Given that dendritic pattern is a fundamental determinant of neuronal wiring, it is not surprising that CSN has been found compromised in several mental retardation syndromes and neurodegenerative diseases [32], [33], [34], [35], [36], [37], [38], [39], [40], [41].…”

Section: Discussionmentioning

confidence: 99%

“…Compromised function of the CSN pathway has been detected in several mental retardation syndromes and neurodegenerative diseases such as Smith-Magenis syndrome, Down syndrome, Alzheimer's disease and Parkinson's disease, Machado-Joseph disease, X-linked mental retardation syndrome [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. However, the functional and mechanistic implications of CSN in neuronal development remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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COP9 Limits Dendritic Branching via Cullin3-Dependent Degradation of the Actin-Crosslinking BTB-Domain Protein Kelch

Djagaeva

Doronkin

2009

PLoS ONE

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Components of the COP9 signalosome (CSN), a key member of the conserved 26S proteasome degradation pathway, have been detected to be altered in patients of several debilitating syndromes. These findings suggest that CSN acts in neural circuits, but the exact function of CSN in brain remains unidentified. Previously, using Drosophila peripheral nervous system (PNS) as a model system, we determined that CSN is a critical regulator of dendritic morphogenesis. We found that defects in CSN led to the strikingly contrast phenotype of either reducing or stimulating dendritic branching. In particular, we have reported that CSN stimulates dendritic branching via Cullin1-mediated proteolysis. Here we describe that CSN inhibits dendritic arborization in PNS neurons acting via control of Cullin3 function: loss of Cullin3 causes excessive dendritic branching. We also identified a downstream target for Cullin3-dependent degradation in neurons – the actin-crosslinking BTB-domain protein Kelch. Inappropriate accumulation of Kelch, either due to the impaired Cullin3-dependent turnover, or ectopic expression of Kelch, leads to uncontrolled dendritic branching. These findings indicate that the CSN pathway modulates neuronal network in a multilayer manner, providing the foundation for new insight into the CSN role in human mental retardation disorders and neurodegenerative disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

COP9 Limits Dendritic Branching via Cullin3-Dependent Degradation of the Actin-Crosslinking BTB-Domain Protein Kelch

Djagaeva

Doronkin

2009

PLoS ONE

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“…In particular, altered components of the COP9 signalosome have been detected in Smith-Magenis syndrome [29], [31], Down syndrome [33], Alzheimer's disease and Parkinson's disease [34], Machado-Joseph neurodegenerative disease [36], [37], and X-linked mental retardation syndrome [38], [39]. The detection in our study of Cubitus interruptus in dendritic morphogenesis is intriguing, because Ci has also been reported to be involved in neurological disease.…”

Section: Discussionmentioning

confidence: 51%

“…In particular, subunit 3 of the COP9 signalosome, CSN3, was reported to be associated with Smith-Magenis syndrome, a multiple congenital anomaly/mental retardation syndrome in autism spectrum disorders [29], [30], [31], [32]. It appears also that CSN is involved, directly or not, in Down syndrome, one of the most frequently isolated causes of mental retardation.…”

Section: Introductionmentioning

confidence: 99%

Dual Regulation of Dendritic Morphogenesis in Drosophila by the COP9 Signalosome

Djagaeva

Doronkin

2009

PLoS ONE

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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.

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“…All CSN subunits are essential for full function of the complex and are produced in free-form before coordinated complex assembling 25,26 . Heterozygous deletion of CSN3 is the molecular cause of Smith–Magenis syndrome that results in reduction of the amount of the CSN protein complex 50 , according to the functional role of CSN3 for the CSN complex stabilization 33 .…”

Section: Discussionmentioning

confidence: 99%

The CSN3 subunit of the COP9 signalosome interacts with the HD region of Sos1 regulating stability of this GEF protein

et al. 2019

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Sos1 is an universal, widely expressed Ras guanine nucleotide-exchange factor (RasGEF) in eukaryotic cells. Its N-terminal HD motif is known to be involved in allosteric regulation of Sos1 GEF activity through intramolecular interaction with the neighboring PH domain. Here, we searched for other cellular proteins also able to interact productively with the Sos1 HD domain. Using a yeast two-hybrid system, we identified the interaction between the Sos1 HD region and CSN3, the third component of the COP9 signalosome, a conserved, multi-subunit protein complex that functions in the ubiquitin–proteasome pathway to control degradation of many cellular proteins. The interaction of CSN3 with the HD of Sos1 was confirmed in vitro by GST pull-down assays using truncated mutants and reproduced in vivo by co-immunoprecipitation with the endogenous, full-length cellular Sos1 protein. In vitro kinase assays showed that PKD, a COP9 signalosome-associated-kinase, is able to phosphorylate Sos1. The intracellular levels of Sos1 protein were clearly diminished following CSN3 or PKD knockdown. A sizable fraction of the endogenous Sos1 protein was found ubiquitinated in different mammalian cell types. A significant reduction of RasGTP formation upon growth factor stimulation was also observed in CSN3-silenced as compared with control cells. Our data suggest that the interaction of Sos1 with the COP9 signalosome and PKD plays a significant role in maintenance of cellular Sos1 protein stability and homeostasis under physiological conditions and raises the possibility of considering the CSN/PKD complex as a potential target for design of novel therapeutic drugs.

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Hemizygosity for the COP9 signalosome subunit gene,SGN3, in the Smith-Magenis syndrome

Cited by 24 publications

References 25 publications

COP9 Limits Dendritic Branching via Cullin3-Dependent Degradation of the Actin-Crosslinking BTB-Domain Protein Kelch

COP9 Limits Dendritic Branching via Cullin3-Dependent Degradation of the Actin-Crosslinking BTB-Domain Protein Kelch

Dual Regulation of Dendritic Morphogenesis in Drosophila by the COP9 Signalosome

The CSN3 subunit of the COP9 signalosome interacts with the HD region of Sos1 regulating stability of this GEF protein

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