DCAF6 reprograms TGF-β responses through TRIM33 destruction
6 affiliations
- 1Ministry of Education Key Laboratory of Biosystems Homeostasis and Protection and Zhejiang Key Laboratory of Molecular Cancer Biology, Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
- 2Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing 321000, Zhejiang, China
- 3Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China
- 4Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang, China
- 5Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala 751 23, Sweden
- 6The Second Affiliated Hospital, Zhejiang University, Hangzhou 310009, Zhejiang, China
Abstract
TGF-β signaling plays a pivotal role in regulating numerous cellular processes, primarily through the Smad-dependent pathway. Disruptions of the pathway are associated with developmental disorders and life-threatening diseases, such as cancer. It has been reported that TRIM33 inactivates Smad4 signaling and also drives its own signaling responses. However, the mechanism controlling TRIM33 activity has remained unclear. In this study, we identify DCAF6 as a previously unrecognized ubiquitin ligase for TRIM33. DCAF6 targets TRIM33 at Lys850 for ubiquitin-dependent proteasomal degradation, thus abolishing TRIM33-mediated mono-ubiquitination of Smad4. As such, DCAF6 induces dual consequences: it enhances Smad4-dependent transcriptional and growth inhibitory responses, while simultaneously eliminating TRIM33-dependent developmental responses. Conversely, DCAF6 knockout suppresses Smad4-dependent responses while amplifying TRIM33-dependent responses. Therefore, DCAF6 operates as a critical regulator in the balance of TGF-β signaling between the Smad4 and TRIM33 pathways. These insights deepen our understanding of the dynamics and fate control of TGF-β signaling and may open avenues for therapeutic approaches targeting TGF-β in diseases.
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BibTeX
@article{luo2026dcaf6,
title = {{DCAF6 reprograms TGF-β responses through TRIM33 destruction}},
author = {Hongjie Luo and Bo Yuan and Jinquan Liu and Zeda Yao and Huanyu Hong and Dachuan Lin and Shuyi Zhang and Jiayi Qian and Jie Li and Jin Cao and Xia Lin and Bin Zhao and Pinglong Xu and Carl-Henrik Heldin and Jianping Jin and Yi Yu and Xin-Hua Feng},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2602333123},
url = {https://doi.org/10.1073/pnas.2602333123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - DCAF6 reprograms TGF-β responses through TRIM33 destruction
AU - Hongjie Luo
AU - Bo Yuan
AU - Jinquan Liu
AU - Zeda Yao
AU - Huanyu Hong
AU - Dachuan Lin
AU - Shuyi Zhang
AU - Jiayi Qian
AU - Jie Li
AU - Jin Cao
AU - Xia Lin
AU - Bin Zhao
AU - Pinglong Xu
AU - Carl-Henrik Heldin
AU - Jianping Jin
AU - Yi Yu
AU - Xin-Hua Feng
PY - 2026
DA - 2026/10/28
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2602333123
UR - https://doi.org/10.1073/pnas.2602333123
AB - TGF-β signaling plays a pivotal role in regulating numerous cellular processes, primarily through the Smad-dependent pathway. Disruptions of the pathway are associated with developmental disorders and life-threatening diseases, such as cancer. It has been reported that TRIM33 inactivates Smad4 signaling and also drives its own signaling responses. However, the mechanism controlling TRIM33 activity has remained unclear. In this study, we identify DCAF6 as a previously unrecognized ubiquitin ligase for TRIM33. DCAF6 targets TRIM33 at Lys850 for ubiquitin-dependent proteasomal degradation, thus abolishing TRIM33-mediated mono-ubiquitination of Smad4. As such, DCAF6 induces dual consequences: it enhances Smad4-dependent transcriptional and growth inhibitory responses, while simultaneously eliminating TRIM33-dependent developmental responses. Conversely, DCAF6 knockout suppresses Smad4-dependent responses while amplifying TRIM33-dependent responses. Therefore, DCAF6 operates as a critical regulator in the balance of TGF-β signaling between the Smad4 and TRIM33 pathways. These insights deepen our understanding of the dynamics and fate control of TGF-β signaling and may open avenues for therapeutic approaches targeting TGF-β in diseases.
SN - 0027-8424
SN - 1091-6490
ER -