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Peer-reviewedCC BY-NC-ND 4.0Cellular and Molecular Life Sciences: CMLS

Ubiquitination of parkin influences its tumor suppressive function in cervical cancer

  • Yuanyuan Mai1,2
  • Hui Hua1,2
  • Shicong Liang3,4
  • Guiqin Ye5
  • Sangni Qian2
  • Zixuan Li2
  • Wenjie Zeng6
  • Xiaoyan Chen6
  • Qinghui Zheng7
  • Huafeng Shou6
  • Jianbin Zhang2
7 affiliations
  1. 1The Second School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053 Zhejiang China
  2. 2Department of Medical Oncology, Cancer Center, Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Affiliated People’s Hospital, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
  3. 3The Affiliated Brain Hospital, Guangzhou Medical University, Guangzhou, 510370 Guangdong China
  4. 4Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, 510370 Guangdong China
  5. 5Department of Clinical Laboratory, Yuhuan City People’s Hospital, Taizhou, 318000 Zhejiang China
  6. 6Department of Gynecology, Affiliated People’s Hospital, Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
  7. 7General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014 Zhejiang China
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Abstract

Parkin is an E3 ubiquitin ligase and its function is primarily regulated by its phosphorylation, yet the role of Parkin ubiquitination remains unclear. Here, we identified the Parkin ubiquitination site at lysine 27 (K27) by mass spectrometry. CHX chase assay confirmed that Parkin ubiquitination-deficient mutant (K27R) exhibited the reduction of Parkin stability. Meanwhile, USP10 was validated as a deubiquitinating enzyme regulating Parkin. Importantly, the Parkin mutant also showed the impaired mitochondrial translocation and the diminished interaction with PINK1, indicating the decreased Parkin phosphorylation. Reciprocally, the Parkin phosphorylation-deficient mutant (S65A) reduced the Parkin ubiquitination level, revealing an interplay between Parkin ubiquitination and its phosphorylation. Functionally, the Parkin mutant elevated the levels of mitochondrial membrane proteins, indicating the impaired mitophagy, which subsequently triggered the release of mitochondrial DNA (mtDNA) and the activation of the cGAS‑STING pathway. Moreover, the Parkin mutant suppressed the oxidative phosphorylation while it markedly enhanced the intracellular glycolysis. Finally, the Parkin mutant promoted the tumor spheroid formation and accelerated tumor growth in vivo, demonstrating the loss of its tumor-suppressive function. Collectively, our findings revealed that Parkin ubiquitination governs its stability and its function in cervical cancer, and may serve as a potential biomarker and therapeutic target.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00018-026-06362-3.

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Cite

BibTeXRIS
BibTeX
@article{mai2026ubiquitination,
  title = {{Ubiquitination of parkin influences its tumor suppressive function in cervical cancer}},
  author = {Yuanyuan Mai and Hui Hua and Shicong Liang and Guiqin Ye and Sangni Qian and Zixuan Li and Wenjie Zeng and Xiaoyan Chen and Qinghui Zheng and Huafeng Shou and Jianbin Zhang},
  journal = {Cellular and Molecular Life Sciences: CMLS},
  year = {2026},
  month = aug,
  doi = {10.1007/s00018-026-06362-3},
  url = {https://doi.org/10.1007/s00018-026-06362-3},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Ubiquitination of parkin influences its tumor suppressive function in cervical cancer
AU  - Yuanyuan Mai
AU  - Hui Hua
AU  - Shicong Liang
AU  - Guiqin Ye
AU  - Sangni Qian
AU  - Zixuan Li
AU  - Wenjie Zeng
AU  - Xiaoyan Chen
AU  - Qinghui Zheng
AU  - Huafeng Shou
AU  - Jianbin Zhang
PY  - 2026
DA  - 2026/08/26
JO  - Cellular and Molecular Life Sciences: CMLS
DO  - 10.1007/s00018-026-06362-3
UR  - https://doi.org/10.1007/s00018-026-06362-3
AB  - Parkin is an E3 ubiquitin ligase and its function is primarily regulated by its phosphorylation, yet the role of Parkin ubiquitination remains unclear. Here, we identified the Parkin ubiquitination site at lysine 27 (K27) by mass spectrometry. CHX chase assay confirmed that Parkin ubiquitination-deficient mutant (K27R) exhibited the reduction of Parkin stability. Meanwhile, USP10 was validated as a deubiquitinating enzyme regulating Parkin. Importantly, the Parkin mutant also showed the impaired mitochondrial translocation and the diminished interaction with PINK1, indicating the decreased Parkin phosphorylation. Reciprocally, the Parkin phosphorylation-deficient mutant (S65A) reduced the Parkin ubiquitination level, revealing an interplay between Parkin ubiquitination and its phosphorylation. Functionally, the Parkin mutant elevated the levels of mitochondrial membrane proteins, indicating the impaired mitophagy, which subsequently triggered the release of mitochondrial DNA (mtDNA) and the activation of the cGAS‑STING pathway. Moreover, the Parkin mutant suppressed the oxidative phosphorylation while it markedly enhanced the intracellular glycolysis. Finally, the Parkin mutant promoted the tumor spheroid formation and accelerated tumor growth in vivo, demonstrating the loss of its tumor-suppressive function. Collectively, our findings revealed that Parkin ubiquitination governs its stability and its function in cervical cancer, and may serve as a potential biomarker and therapeutic target.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00018-026-06362-3.
SN  - 1420-682X
SN  - 1420-9071
ER  -