دورية أكاديمية
The ubiquitin E3 ligase APC/C Cdc20 mediates mitotic degradation of OGT.
| العنوان: | The ubiquitin E3 ligase APC/C Cdc20 mediates mitotic degradation of OGT. |
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| المؤلفون: | Meng L; Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China., Dong R; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China., Mi W; Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China., Qin K; College of Chemistry and Molecular Engineering, Beijing National Laboratory for Molecular Sciences, Peking-Tsinghua Center for Life Sciences, Synthetic and Functional Biomolecules Center, and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing, China., Ouyang K; Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, Shenzhen, China. Electronic address: ouyang_kunfu@pku.edu.cn., Sun J; State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China. Electronic address: jwsun@ynu.edu.cn., Li J; Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, China. Electronic address: jing_li@mail.cnu.edu.cn. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2024 Jul; Vol. 300 (7), pp. 107448. Date of Electronic Publication: 2024 Jun 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Mitosis* , N-Acetylglucosaminyltransferases*/metabolism , N-Acetylglucosaminyltransferases*/genetics , Ubiquitination* , Anaphase-Promoting Complex-Cyclosome*/metabolism , Anaphase-Promoting Complex-Cyclosome*/genetics, Humans ; Animals ; Cdc20 Proteins/metabolism ; Cdc20 Proteins/genetics ; Mice ; Proteolysis ; HeLa Cells ; HEK293 Cells ; Female |
| مستخلص: | O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is the sole enzyme that catalyzes all O-GlcNAcylation reactions intracellularly. Previous investigations have found that OGT levels oscillate during the cell division process. Specifically, OGT abundance is downregulated during mitosis, but the underlying mechanism is lacking. Here we demonstrate that OGT is ubiquitinated by the ubiquitin E3 ligase, anaphase promoting complex/cyclosome (APC/C)-cell division cycle 20 (Cdc20). We show that APC/C Cdc20 interacts with OGT through a conserved destruction box (D-box): Arg-351/Leu-354, the abrogation of which stabilizes OGT. As APC/C Cdc20 -substrate binding is often preceded by a priming ubiquitination event, we also used mass spectrometry and mapped OGT Lys-352 to be a ubiquitination site, which is a prerequisite for OGT association with APC/C subunits. Interestingly, in The Cancer Genome Atlas, R351C is a uterine carcinoma mutant, suggesting that mutations of the D-box are linked with tumorigenesis. Paradoxically, we found that both R351C and the D-box mutants (R351A/L354A) inhibit uterine carcinoma in mouse xenograft models, probably due to impaired cell division and proliferation. In sum, we propose a model where OGT Lys-352 ubiquitination primes its binding with APC/C, and then APC/C Cdc20 partners with OGT through the D-box for its mitotic destruction. Our work not only highlights the key mechanism that regulates OGT during the cell cycle, but also reveals the mutual coordination between glycosylation and the cell division machinery. Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: APC/C(Cdc20); OGT; cell cycle; ubiquitination; uterine carcinoma |
| المشرفين على المادة: | EC 2.4.1.- (N-Acetylglucosaminyltransferases) EC 2.4.1.255 (OGT protein, human) EC 2.3.2.27 (Anaphase-Promoting Complex-Cyclosome) 0 (Cdc20 Proteins) 156288-95-8 (CDC20 protein, human) |
| تواريخ الأحداث: | Date Created: 20240606 Date Completed: 20240725 Latest Revision: 20240725 |
| رمز التحديث: | 20240726 |
| مُعرف محوري في PubMed: | PMC11261447 |
| DOI: | 10.1016/j.jbc.2024.107448 |
| PMID: | 38844135 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2024.107448 |