2. Academic Validation
  3. The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region

The deubiquitinase OTUD1 noncanonically suppresses Akt activation through its N-terminal intrinsically disordered region

  • Cell Rep. 2023 Jan 31;42(1):111916. doi: 10.1016/j.celrep.2022.111916.
Guanlan Fan 1,  Fan Wang 2,  Yurou Chen 1,  Qian Zheng 2,  Jie Xiong 3,  Qiongying Lv 1,  Kejia Wu 1,  Jiaqiang Xiong 1,  Lei Wei 4,  Dongqing Li 5,  Jiachen Zhang 2,  Wei Zhang 6,  Feng Li 7
Affiliations

Affiliations

  • 1 Department of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 2 Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 4 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 5 Department of Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 6 Department of Gynecology and Obstetrics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 7 Department of Medical Genetics, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Allergy and Immunology, Wuhan 430071, China. Electronic address: [email protected].
PMID: 36640312 DOI: 10.1016/j.celrep.2022.111916
Abstract

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.

Keywords

Akt signaling pathway; CP: Cancer; CP: Molecular biology; targeted therapies; tumour-suppressor protein OTUD1.

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