E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration

Upadhyay, Arun; Joshi, Vibhuti; Amanullah, Ayeman; Mishra, Ribhav; Arora, Naina; Prasad, Amit; Mishra, Amit Kumar

doi:10.3389/fnmol.2017.00151

Cited by 66 publications

(63 citation statements)

References 294 publications

(324 reference statements)

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“…RLIM is an E3 ubiquitin ligase and plays together with other proteins a crucial role within the ubiquitin-proteasome system (UPS), and several ligases and coenzymes within the UPS play an important role in the spatial and temporal control of protein turnover in the nervous system [44]. The UPS regulates the development and maintenance of specialized neuronal structures, and consequently, neuronal transmission.…”

Section: Discussionmentioning

confidence: 99%

“…The UPS regulates the development and maintenance of specialized neuronal structures, and consequently, neuronal transmission. Its dysregulation leads to various movement disturbances, dementia and hypogonadotropic hypogonadism [44,45]. Thus, it is not surprising that a growing group of ID proteins are directly involved in UPS-mediated protein degradation, such as UBE3A [46] [47], UBE2A [48,49,50,51], UBE3B [52,47], HUWE1 [53,54,55], MID1 [56][57][58][59], CUL4B [60,[61][62][63], UBR1 [64,65,66], TRIP12 [67][68][69], and RNF216 [45,[70][71][72].…”

Section: Discussionmentioning

confidence: 99%

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Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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“…Cellular proteome is a well‐regulated interconnected network of proteins where small perturbations in the functions of these regulator proteins may result in severe abnormalities or pathogenic conditions . UPS consists of an array of proteins forming a large network that are directly or indirectly connected to most, if not all, of the other cellular pathways; and therefore, intricate implication of such proteins in the molecular pathomechanism of several types of diseases, from development to degeneration, has been widely explored . However, a tight regulation provided by UPS over the turnover and activity of several of its substrates avoids multiple such diseases to occur.…”

Section: Proteasomal System: Failure May Drive Onset Of Several Diseasesmentioning

confidence: 99%

Proteasome‐mediated proteostasis: Novel medicinal and pharmacological strategies for diseases

Mishra

Upadhyay

Prajapati

et al. 2018

Medicinal Research Reviews

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Proteins actively participate in a wide range of cellular physiological functions. But aggregation of proteins results in cytotoxicity, and unwanted aggregation of misfolded proteins often causes many diseases. During abnormal protein aggregation events, cells try to cope against such deleterious consequences because of the remarkable functional attempts of two distinct proteolytic mechanisms. These tightly regulative and signaling mechanisms are autophagy pathway and ubiquitin proteasome system. Proteasome complex system holds the elimination capacity of intracellular aberrant protein aggregation. Despite the considerable progress that has been achieved, which elucidates wide function and diverse roles of proteasome system, still several crucial problems remain unanswered. For example, how the complex proteasomes assembly and their interactive pathways determine the precise sense of several proteotoxic insults, which can severely affect the cell survival and homeostasis? The specific degradation of various aberrant proteins that can disturb cellular homeostasis is achieved by proper proteasome functionality, which is yet another unclear and critical challenge. Therefore, a better understanding of the various cellular signaling mechanisms composing the proteasome machinery carries broad therapeutic implications linked with proteopathies. This article signifies the urgent need, which is now crucial for us to improve our understanding of the proteasome architecture, structure, and functions that span multiple level strategies from the molecular level to the cellular level. This systematic in-depth information of proteasome may be helpful in the near future to design a new molecular framework based on intrinsic and extrinsic cellular mechanisms that drive the assembly of proteasome to induce cellular survival against proteostasis imbalance and disease conditions.

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“…The E3 ub ligases are responsible for recognizing and recruiting target proteins for ubiquitination, and thus, they confer substrate specificity to UPS (Upadhyay et al . ). Recently, increasing number of E3 ub ligases has been reported to modulate polyQ toxicity through promoting ubiquitination and degradation of polyQ proteins in cultured cells and transgenic animal models (Bhat et al .…”

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confidence: 97%

FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

Chen

Wong

Cheng

et al. 2019

Journal of Neurochemistry

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Polyglutamine (polyQ) diseases describe a group of progressive neurodegenerative disorders caused by the CAG triplet repeat expansion in the coding region of the disease genes. To date, nine such diseases, including spinocerebellar ataxia type 3 (SCA3), have been reported. The formation of SDS‐insoluble protein aggregates in neurons causes cellular dysfunctions, such as impairment of the ubiquitin‐proteasome system, and contributes to polyQ pathologies. Recently, the E3 ubiquitin ligases, which govern substrate specificity of the ubiquitin‐proteasome system, have been implicated in polyQ pathogenesis. The Cullin (Cul) proteins are major components of Cullin‐RING ubiquitin ligases (CRLs) complexes that are evolutionarily conserved in the Drosophila genome. In this study, we examined the effect of individual Culs on SCA3 pathogenesis and found that the knockdown of Cul1 expression enhances SCA3‐induced neurodegeneration and reduces the solubility of expanded SCA3‐polyQ proteins. The F‐box proteins are substrate receptors of Cul1‐based CRL. We further performed a genetic modifier screen of the 19 Drosophila F‐box genes and identified F‐box involved in polyQ pathogenesis (FipoQ) as a genetic modifier of SCA3 degeneration that modulates the ubiquitination and solubility of expanded SCA3‐polyQ proteins. In the human SK‐N‐MC cell model, we identified that F‐box only protein 33 (FBXO33) exerts similar functions as FipoQ in modulating the ubiquitination and solubility of expanded SCA3‐polyQ proteins. Taken together, our study demonstrates that Cul1‐based CRL and its associated F‐box protein, FipoQ/FBXO33, modify SCA3 protein toxicity. These findings will lead to a better understanding of the disease mechanism of SCA3 and provide insights for developing treatments against SCA3. Cover Image for this issue: doi: .

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E3 Ubiquitin Ligases Neurobiological Mechanisms: Development to Degeneration

Cited by 66 publications

References 294 publications

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Proteasome‐mediated proteostasis: Novel medicinal and pharmacological strategies for diseases

FipoQ/FBXO33, a Cullin‐1‐based ubiquitin ligase complex component modulates ubiquitination and solubility of polyglutamine disease protein

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