Ubiquitin-protein ligase E3C promotes glioma progression by mediating the ubiquitination and degrading of Annexin A7

Pan, Si Jian; Zhan, Shi; Ji, Wei; Pan, Yixin; Liu, Wei; Li, Dian You; Huang, Peng; Zhang, Xiao; Cao, Chun; Zhang, Jing; Bian, Liu Guan; Sun, Bomin; Sun, Qing

doi:10.1038/srep11066

Cited by 33 publications

(30 citation statements)

References 33 publications

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“…The UBE3C ubiquitin ligase is involved in myriad cellular processes, such as proteasome processivity, interferon signaling, and cancer metastasis [11,12]. In summary (Figure 8), we solved the crystal structure of WT UBE3C HECT domain (aa 693-1083) at 2.7 Å and showed that the N-terminal extended region (aa 693-743)…”

Section: Discussionmentioning

confidence: 92%

“…UBE3C (aa 1-1083), also known as RTA-associated ubiquitin ligase (RAUL), is a member of the 'other' subfamily of HECT E3 ligases. It contains an 'IQ' motif (aa 45-74) at its N-terminus and a HECT domain (aa 744-1083) at its C-terminus, which regulates several crucial cellular processes [11,12]. The HECT domain of UBE3C displays ∼30% sequence identity with the HECT domains of NEDD4 subfamily members, and ∼32% sequence identity with the HECT domains of the 'other' subfamily members.…”

Section: Introductionmentioning

confidence: 99%

“…This allows for rapid viral growth and leaves the host immunocompromised. Other studies have shown that abrupt activation of UBE3C is associated with epithelial-mesenchymal transition, which is associated with the progression of melanoma and glioma [11]. Despite the versatile nature of UBE3C-mediated ubiquitination and its involvement in disease processes, the structure, and ubiquitination mechanism of this E3 ligase is not available.…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure of HECT domain of UBE3C E3 ligase and its ubiquitination activity

Singh

Sivaraman

2020

Biochemical Journal

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The HECT family of E3 ubiquitin ligase is divided into three subfamilies: the NEDD4, the HERC, and the 'other'. Previous studies have mostly targeted members of the NEDD4 subfamily for structural and functional analysis. The UBE3C E3 ligase is a member of the 'other' subfamily HECT and influences several crucial cellular processes, including innate immunity, proteasome processivity, and cancer metastasis. Here, we report the crystal structure of the HECT domain of UBE3C (amino acids (aa) 744-1083) with an additional fifty N-terminal amino acids (aa 693-743) at 2.7 Å, along with multiple in vitro ubiquitination assays to understand its enzymatic activity. The UBE3C HECT domain forms an open, L-shaped, bilobed conformation, having a large N-lobe and a small C-lobe. We show that the N-terminal region (aa 693-743) preceding the UBE3C HECT domain as well as a loop region (aa 758-762) in the N-lobe of the HECT domain affect the stability and activity of UBE3C HECT domain. Moreover, we identified Lys903 in the UBE3C HECT domain as a major site of autoubiquitination. The deletion of the last three amino acids at the C-terminal completely abrogated UBE3C activity while mutations of Gln961 and Ser1049 residues in the HECT domain substantially decreased its autoubiquitination activity. We demonstrate that these region/residues are involved in the E2-E3 transthiolation process and affect the UBE3C mediated autoubiquitination. Collectively, our study identified key residues crucial for UBE3C enzymatic activity, and it may assist in the development of suitable inhibitors to regulate its activity in multiple cancers.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crystal structure of HECT domain of UBE3C E3 ligase and its ubiquitination activity

Singh

Sivaraman

2020

Biochemical Journal

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“…For example, ANXA7 is a tumor suppressor protein. The expression of this protein is decreased in glioma tissues, and its degradation may contribute to glioma progression [18]. Moreover, loss of ANXA7 is associated with prognosis in glioblastoma patients, and ANXA7 is a strong predictor of patient outcome [33,34].…”

Section: Discussionmentioning

confidence: 99%

Urinary biomarker discovery in gliomas using mass spectrometry-based clinical proteomics

Zhang

Wei

et al. 2020

Chin Neurosurg Jl

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Background: Gliomas are the most common primary malignant brain tumors and have a poor prognosis. Early detection of gliomas is crucial to improve patient outcomes. Urine accumulates systematic body changes and thus serves as an excellent early biomarker source. Methods: At the biomarker discovery phase, we performed a self-controlled proteomics analysis by comparing urine samples collected from five glioma patients at the time of tumor diagnosis and after surgical removal of the tumor. At the biomarker validation phase, we further validated some promising proteins using parallel reaction monitoring (PRM)-based targeted proteomics in another cohort, including glioma, meningioma, and moyamoya disease patients as well as healthy controls. Results: Using label-free proteome quantitation (LFQ), we identified twenty-seven urinary proteins that were significantly changed after tumor resection, many of which have been previously associated with gliomas. The functions of these proteins were significantly enriched in the autophagy and angiogenesis, which are associated with glioma development. After targeted proteomics validation, we identified a biomarker panel (AACT, TSP4, MDHM, CALR, LEG1, and AHSG) with an area under the curve (AUC) value of 0.958 for the detection of gliomas. Interestingly, AACT, LEG1, and AHSG are also potential cerebrospinal fluid or blood biomarkers of gliomas. Conclusions: Using LFQ and PRM proteome quantification, we identified candidate urinary protein biomarkers with the potential to detect gliomas. This study will also provide clues for future biomarker studies involving brain diseases.

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“…ANXA7 is a tumor suppressor gene. ANXA7 protein expression decreased in glioma tissues, and ANXA7 degradation might contribute to glioma progression [21]. Furthermore, loss of ANXA7 is associated with glioblastoma patient prognosis, and its expression was a strong predictor of patient outcome [22,23].…”

Section: Discussionmentioning

confidence: 99%

Candidate urine biomarker discovery from only five pairs of samples before and after tumor resection in glioma patients

Zhang

Zhao

et al. 2018

Preprint

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Biomarkers are measurable changes associated with the disease. Without the control of homeostatic mechanisms, urine accumulates systemic body changes and thus serves as an excellent early biomarker source. However, urine is affected by many factors other than disease. Although many candidate biomarkers have been identified in animal models, a large number of clinical samples might still be required for the disease related changes. A self-controlled study should be able to avoid the interferences of individual differences among patients. Gliomas are the most common primary malignant brain tumors and have a very poor prognosis. Early diagnosis of gliomas and the monitoring of tumor recurrence are crucial to improve glioma patient outcomes. Here we set to try if biomarker candidates can be identified by comparing urine samples from five glioma patients collected at the time of tumor diagnosis and after surgical removal of the tumor.Using label-free liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) quantification, twenty-seven urinary proteins were significantly changed after tumor resection (fold change ≥ 1.5, P-value < 0.05, and similar changes in all 5 patients), many of which have been previously associated with gliomas, such as CEACAM1, ANXA7, CALR, CRYAB, CD276, pIgR and cathepsin D. Functions of these proteins were significantly enriched in the regulation of tissue remodeling, autophagy, the inhibition of gene expression, the positive regulation of natural killer cell-mediated cytotoxicity and angiogenesis, which are associated with glioma development. Our results suggested that using the self-control of before and after tumor resection is an effective method to identify differential proteins associated with the disease, even with a small number of patients.

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Ubiquitin-protein ligase E3C promotes glioma progression by mediating the ubiquitination and degrading of Annexin A7

Cited by 33 publications

References 33 publications

Crystal structure of HECT domain of UBE3C E3 ligase and its ubiquitination activity

Crystal structure of HECT domain of UBE3C E3 ligase and its ubiquitination activity

Urinary biomarker discovery in gliomas using mass spectrometry-based clinical proteomics

Candidate urine biomarker discovery from only five pairs of samples before and after tumor resection in glioma patients

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