JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

TAF1 aggravates ferroptosis by promoting ubiquitin-mediated degradation of nGPX4

Author(s): Kehong YE^1, ², Meifu GAN³, Liang SUN¹, Chaoyi CHEN⁴, Xuan LAI¹, Yinjun HE⁵, Ming ZHU¹, Weiqin JIANG⁶, Honghe ZHANG¹
Affiliation(s): ¹Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China ²Department of Pathology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310011, China ³Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou 317000, China ⁴Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China ⁵Department of Pathology, State Key Laboratory of Complex Severe and Rare Disease, Molecular Pathology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China ⁶Department of Colorectal Surgery and Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
Corresponding email(s): Honghe ZHANG, honghezhang@zju.edu.cn Weiqin JIANG, weiqinjiang@zju.edu.cn
Key Words: TATA-box binding protein-associated factor 1 (TAF1); p53; Ferroptosis; Glutathione peroxidase 4 (GPX4); Protein degradation

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Kehong YE^1,², Meifu GAN³, Liang SUN¹, Chaoyi CHEN⁴, Xuan LAI¹, Yinjun HE⁵, Ming ZHU¹, Weiqin JIANG⁶, Honghe ZHANG¹. TAF1 aggravates ferroptosis by promoting ubiquitin-mediated degradation of nGPX4[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500567

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author="Kehong YE^1,², Meifu GAN³, Liang SUN¹, Chaoyi CHEN⁴, Xuan LAI¹, Yinjun HE⁵, Ming ZHU¹, Weiqin JIANG⁶, Honghe ZHANG¹",
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year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500567"
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Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: Glutathione peroxidase 4 (GPX4) is a primary inhibitor of ferroptosis, a regulated form of cell death driven by the accumulation of lipid hydroperoxides. GPX4 exists in three isoforms localized in the cytosol, mitochondria and nucleus, respectively; however, the regulatory mechanisms governing nuclear GPX4 (nGPX4) remain largely unclear. Herein, we identified TATA-box binding protein-associated factor 1 (TAF1) as a pivotal regulator of nGPX4. TAF1 phosphorylates nGPX4, leading to its K11-linked ubiquitination and proteasomal degradation, thereby promoting ferroptosis in p53-mutant cells. Conversely, in p53-wild-type cells, TAF1 phosphorylates p53, facilitating MDM2 proto-oncogene (MDM2)-mediated p53 degradation, which upregulates solute carrier family 7 member 11 (SLC7A11) expression and reduces cellular susceptibility to ferroptosis. Collectively, TAF1 plays dual and context-dependent roles in ferroptosis regulation, acting as both a promoter and inhibitor depending on the p53 status.

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