Related Experiment Video

Updated: Jun 11, 2026

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
09:47

Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates

Published on: May 10, 2022

TRIM21 and OTUD6A orchestrate AKT K27-linked atypical ubiquitination to modulate cancer chemoresistance

Qiwei Jiang1,2, Peipei Song3, Shuishen Zhang4

  • 1Center of Lung Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. jiangqw6@mail.sysu.edu.cn.

Nature Structural & Molecular Biology
|November 4, 2025
PubMed

Insights

The E3 ubiquitin ligase TRIM21 suppresses tumors by inhibiting AKT activity via K27 ubiquitination, a process opposed by OTUD6A. Targeting this TRIM21-OTUD6A axis offers a strategy against AKT-driven cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Ubiquitination Signaling

Background:

  • Ubiquitination is crucial for physiological and pathological processes.
  • The role of atypical AKT ubiquitination in tumorigenesis is not well understood.
  • AKT signaling is frequently dysregulated in various cancers.

Purpose of the Study:

  • To investigate the mechanism of atypical AKT ubiquitination.
  • To elucidate the role of TRIM21 and OTUD6A in AKT regulation and tumorigenesis.
  • To explore therapeutic strategies targeting the AKT pathway in cancer.

Main Methods:

  • Investigated AKT ubiquitination using K27-linked chains mediated by TRIM21.
  • Assessed the antagonistic role of deubiquitinase OTUD6A.
  • Utilized a KrasG12D-driven lung cancer mouse model and in vivo studies.

Main Results:

  • TRIM21 ubiquitinates AKT via K27 linkages, inhibiting its kinase activity and membrane localization.
  • OTUD6A antagonizes TRIM21-mediated AKT suppression; S6K1 phosphorylates and inactivates OTUD6A.
  • Otud6a deficiency reduced lung tumorigenesis; TRIM21 induction suppressed tumor growth in vivo.

Conclusions:

  • Atypical K27 ubiquitination by TRIM21 fine-tunes AKT activity, acting as a tumor suppressor.
  • The TRIM21-OTUD6A axis represents a novel regulatory mechanism for AKT.
  • Targeting the TRIM21-OTUD6A axis is a potential therapeutic strategy for AKT-driven cancers.

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