The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region
Summary: Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124722018150 |
| _version_ | 1797961091382247424 |
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| author | Guanlan Fan Fan Wang Yurou Chen Qian Zheng Jie Xiong Qiongying Lv Kejia Wu Jiaqiang Xiong Lei Wei Dongqing Li Jiachen Zhang Wei Zhang Feng Li |
| author_facet | Guanlan Fan Fan Wang Yurou Chen Qian Zheng Jie Xiong Qiongying Lv Kejia Wu Jiaqiang Xiong Lei Wei Dongqing Li Jiachen Zhang Wei Zhang Feng Li |
| author_sort | Guanlan Fan |
| collection | DOAJ |
| description | Summary: Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to this effect. A short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. The residues in the PH domain, which are required for PtdIns(3,4,5)P3 recognition, are also essential for OUN-36 binding. OUN-36 preferentially inhibits Akt-hyperactive tumor cells’ proliferation and interferes with Akt cell membrane localization, presumably by disrupting PH domain-PIP3 interaction. Importantly, OUN-36-based therapy efficiently abrogates Akt feedback reactivation in response to MK-2206 treatment and sensitizes cancer cells to chemotherapy and immunotherapy. We therefore show a mechanism by which OTUD1 modulates Akt activity and suggest a potential peptide-based cancer therapeutic strategy implemented by targeting the Akt PH domain. |
| first_indexed | 2024-04-11T00:53:57Z |
| format | Article |
| id | doaj.art-07864f7b38ed462c8a59f90257793431 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-11T00:53:57Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-07864f7b38ed462c8a59f902577934312023-01-05T06:23:59ZengElsevierCell Reports2211-12472023-01-01421111916The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered regionGuanlan Fan0Fan Wang1Yurou Chen2Qian Zheng3Jie Xiong4Qiongying Lv5Kejia Wu6Jiaqiang Xiong7Lei Wei8Dongqing Li9Jiachen Zhang10Wei Zhang11Feng Li12Department of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, ChinaDepartment of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, ChinaDepartment of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, ChinaDepartment of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, ChinaDepartment of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, ChinaDepartment of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, ChinaDepartment of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, ChinaDepartment of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, ChinaDepartment of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, ChinaDepartment of Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, ChinaDepartment of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, ChinaDepartment of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Corresponding authorDepartment of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China; Corresponding authorSummary: Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to this effect. A short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. The residues in the PH domain, which are required for PtdIns(3,4,5)P3 recognition, are also essential for OUN-36 binding. OUN-36 preferentially inhibits Akt-hyperactive tumor cells’ proliferation and interferes with Akt cell membrane localization, presumably by disrupting PH domain-PIP3 interaction. Importantly, OUN-36-based therapy efficiently abrogates Akt feedback reactivation in response to MK-2206 treatment and sensitizes cancer cells to chemotherapy and immunotherapy. We therefore show a mechanism by which OTUD1 modulates Akt activity and suggest a potential peptide-based cancer therapeutic strategy implemented by targeting the Akt PH domain.http://www.sciencedirect.com/science/article/pii/S2211124722018150CP: Molecular biologyCP: Cancer |
| spellingShingle | Guanlan Fan Fan Wang Yurou Chen Qian Zheng Jie Xiong Qiongying Lv Kejia Wu Jiaqiang Xiong Lei Wei Dongqing Li Jiachen Zhang Wei Zhang Feng Li The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region Cell Reports CP: Molecular biology CP: Cancer |
| title | The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region |
| title_full | The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region |
| title_fullStr | The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region |
| title_full_unstemmed | The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region |
| title_short | The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region |
| title_sort | deubiquitinase otud1 noncanonically suppresses akt activation through its n terminal intrinsically disordered region |
| topic | CP: Molecular biology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124722018150 |
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