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
  • 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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