Predicting E3 Ubiquitin Ligases as Possible Promising Biomarkers for Brain Tumors

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

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TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Cells ◽

10.3390/cells10040820 ◽

2021 ◽

Vol 10 (4) ◽

pp. 820

Author(s):

Lorena Kumarasinghe ◽

Lu Xiong ◽

Maria Adelaida Garcia-Gimeno ◽

Elisa Lazzari ◽

Pascual Sanz ◽

...

Keyword(s):

Common Ancestor ◽

Genetic Diseases ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Lafora Disease ◽

C Terminus ◽

Rare Genetic Diseases ◽

Tripartite Motif ◽

Trim Proteins ◽

Ring E3

Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

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Regulation of Notch signaling by E3 ubiquitin ligases

FEBS Journal ◽

10.1111/febs.15792 ◽

2021 ◽

Author(s):

Debdeep Dutta ◽

Vartika Sharma ◽

Mousumi Mutsuddi ◽

Ashim Mukherjee

Keyword(s):

Notch Signaling ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases

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Classification and interaction modes of 40 rice E2 ubiquitin-conjugating enzymes with 17 rice ARM-U-box E3 ubiquitin ligases

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2014.01.098 ◽

2014 ◽

Vol 444 (4) ◽

pp. 575-580 ◽

Cited By ~ 23

Author(s):

Hansol Bae ◽

Woo Taek Kim

Keyword(s):

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

Conjugating Enzymes ◽

Ubiquitin Conjugating Enzymes

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Comprehensive database of human E3 ubiquitin ligases: application to aquaporin-2 regulation

Physiological Genomics ◽

10.1152/physiolgenomics.00031.2016 ◽

2016 ◽

Vol 48 (7) ◽

pp. 502-512 ◽

Cited By ~ 31

Author(s):

Barbara Medvar ◽

Viswanathan Raghuram ◽

Trairak Pisitkun ◽

Abhijit Sarkar ◽

Mark A. Knepper

Keyword(s):

Human Genome ◽

Large Scale ◽

E3 Ligase ◽

Ubiquitin Ligases ◽

Bayes Rule ◽

E3 Ubiquitin Ligases ◽

E3 Ligases ◽

Aquaporin 2 ◽

Large Scale Data ◽

Level Data

Aquaporin-2 (AQP2) is regulated in part via vasopressin-mediated changes in protein half-life that are in turn dependent on AQP2 ubiquitination. Here we addressed the question, “What E3 ubiquitin ligase is most likely to be responsible for AQP2 ubiquitination?” using large-scale data integration based on Bayes' rule. The first step was to bioinformatically identify all E3 ligase genes coded by the human genome. The 377 E3 ubiquitin ligases identified in the human genome, consisting predominant of HECT, RING, and U-box proteins, have been used to create a publically accessible and downloadable online database ( https://hpcwebapps.cit.nih.gov/ESBL/Database/E3-ligases/ ). We also curated a second database of E3 ligase accessory proteins that included BTB domain proteins, cullins, SOCS-box proteins, and F-box proteins. Using Bayes' theorem to integrate information from multiple large-scale proteomic and transcriptomic datasets, we ranked these 377 E3 ligases with respect to their probability of interaction with AQP2. Application of Bayes' rule identified the E3 ligases most likely to interact with AQP2 as (in order of probability): NEDD4 and NEDD4L (tied for first), AMFR, STUB1, ITCH, ZFPL1. Significantly, the two E3 ligases tied for top rank have also been studied extensively in the reductionist literature as regulatory proteins in renal tubule epithelia. The concordance of conclusions from reductionist and systems-level data provides strong motivation for further studies of the roles of NEDD4 and NEDD4L in the regulation of AQP2 protein turnover.

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E3 ubiquitin ligases as T cell anergy factors

Nature Immunology ◽

10.1038/ni1106 ◽

2004 ◽

Vol 5 (9) ◽

pp. 883-890 ◽

Cited By ~ 165

Author(s):

Daniel L Mueller

Keyword(s):

T Cell ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

T Cell Anergy ◽

Cell Anergy

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DDB2 regulates DNA replication through PCNA-independent degradation of CDT2

Cell & Bioscience ◽

10.1186/s13578-021-00540-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaojun Wu ◽

Min Yu ◽

Zhuxia Zhang ◽

Feng Leng ◽

Yue Ma ◽

...

Keyword(s):

Dna Replication ◽

Cancer Therapy ◽

Target Genes ◽

Ubiquitin Ligases ◽

Ovarian Teratoma ◽

Control Group ◽

E3 Ubiquitin Ligases ◽

Small Interfering Rnas ◽

Interacting Protein

Abstract Background Targeting ubiquitin-dependent proteolysis is one of the strategies in cancer therapy. CRLCDT2 and CRLDDB2 are two key E3 ubiquitin ligases involved in DNA replication and DNA damage repair. But CDT2 and DDB2 are opposite prognostic factors in kinds of cancers, and the underlining mechanism needs to be elucidated. Methods Small interfering RNAs were used to determine the function of target genes. Co-immunoprecipitation (Co-IP) was performed to detect the interaction between DDB2 and CDT2. Immunofluorescence assays and fluorescence activating cell sorting (FACS) were used to measure the change of DNA content. In vivo ubiquitination assay was carried out to clarify the ubiquitination of CDT2 mediated by DDB2. Cell synchronization was performed to arrest cells at G1/S and S phase. The mechanism involved in DDB2-mediated CDT2 degradation was investigated by constructing plasmids with mutant variants and measured by Western blot. Immunohistochemistry was performed to determine the relationship between DDB2 and CDT2. Paired two-side Student’s t-test was used to measure the significance of the difference between control group and experimental group. Results Knockdown of DDB2 stabilized CDT2, while over-expression of DDB2 enhanced ubiquitination of CDT2, and subsequentially degradation of CDT2. Although both DDB2 and CDT2 contain PIP (PCNA-interacting protein) box, PIP box is dispensable for DDB2-mediated CDT2 degradation. Knockdown of PCNA had negligible effects on the stability of CDT2, but promoted accumulation of CDT1, p21 and SET8. Silencing of DDB2 arrested cell cycle in G1 phase, destabilized CDT1 and reduced the chromatin loading of MCMs, thereby blocked the formation of polyploidy induced by ablation of CDT2. In breast cancer and ovarian teratoma tissues, high level of DDB2 was along with lower level of CDT2. Conclusions We found that CRL4DDB2 is the novel E3 ubiquitin ligases of CDT2, and DDB2 regulates DNA replication through indirectly regulates CDT1 protein stability by degrading CDT2 and promotes the assembly of pre-replication complex. Our results broaden the horizon for understanding the opposite function of CDT2 and DDB2 in tumorigenesis, and may provide clues for drug discovery in cancer therapy.

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