ArticleNature structural & molecular biology2026
TRIM21 and OTUD6A orchestrate AKT K27-linked atypical ubiquitination to modulate cancer chemoresistance.
Article in Nature structural & molecular biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Phase Separation of TRIM21 Modulates PTPN14 Stability to Drive Flow-Dependent Endothelial Activation and Atherogenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Protein modification systems as cancer biomarkers and therapeutic targets.Precision clinical medicine · 2026Review
- Decoding the crosstalk between ubiquitination and other post-translational modifications in cancer immunity: from mechanisms to clinical prospects.NPJ precision oncology · 2026Review
- SKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives.Drug design, development and therapy · 2026Review
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Authors and funding
16 authors.
Funding
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Abstract
Ubiquitination regulates various physiological and pathological processes. However, the impact of atypical AKT ubiquitination and its potential role in tumorigenesis remain unclear. Here we show that AKT is modified by K27-linked ubiquitination by the E3 ubiquitin ligase TRIM21, a process antagonized by the deubiquitinase OTUD6A. As such, TRIM21 acts as a tumor suppressor by repressing AKT activity, whereas OTUD6A counteracts AKT suppression. Mechanistically, TRIM21-mediated AKT ubiquitination disrupts SKP2-mediated or TRAF6-mediated K63 ubiquitination, thereby blocking AKT membrane localization and its kinase activity. Upon activation in response to amino acids, S6K1 directly phosphorylates and inactivates OTUD6A, enabling a negative feedback loop regulating AKT activity in a deubiquitination-dependent manner. In agreement with this model, Otud6a deficiency reduces lung tumorigenesis in a Kras
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