Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function

Ke Wu; Meisi Yan; Tong Liu; Zheng Wang; Yuran Duan; Yan Xia; Guimei Ji; Yuli Shen; Lei Wang; Lin Li; Peixiang Zheng; Bofei Dong; Qingang Wu; Liwei Xiao; Xueying Yang; Haochen Shen; Ting Wen; Jingjing Zhang; Jinfeng Yi; Yuhan Deng; Xu Qian; Leina Ma; Jing Fang; Qin Zhou; Zhimin Lu; Daqian Xu

doi:10.1038/s41556-023-01133-9

Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function

Ke Wu, Meisi Yan, Tong Liu, Zheng Wang, Yuran Duan, Yan Xia, Guimei Ji, Yuli Shen, Lei Wang, Lin Li, Peixiang Zheng, Bofei Dong, Qingang Wu, Liwei Xiao, Xueying Yang, Haochen Shen, Ting Wen, Jingjing Zhang, Jinfeng Yi, Yuhan DengXu Qian, Leina Ma, Jing Fang, Qin Zhou, Zhimin Lu, Daqian Xu

Neuro-Oncology

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Abstract

Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

Original language	English (US)
Pages (from-to)	714-725
Number of pages	12
Journal	Nature cell biology
Volume	25
Issue number	5
DOIs	https://doi.org/10.1038/s41556-023-01133-9
State	Published - May 2023

ASJC Scopus subject areas

Cell Biology

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Wu, K., Yan, M., Liu, T., Wang, Z., Duan, Y., Xia, Y., Ji, G., Shen, Y., Wang, L., Li, L., Zheng, P., Dong, B., Wu, Q., Xiao, L., Yang, X., Shen, H., Wen, T., Zhang, J., Yi, J., ... Xu, D. (2023). Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function. Nature cell biology, 25(5), 714-725. https://doi.org/10.1038/s41556-023-01133-9

Wu, K, Yan, M, Liu, T, Wang, Z, Duan, Y, Xia, Y, Ji, G, Shen, Y, Wang, L, Li, L, Zheng, P, Dong, B, Wu, Q, Xiao, L, Yang, X, Shen, H, Wen, T, Zhang, J, Yi, J, Deng, Y, Qian, X, Ma, L, Fang, J, Zhou, Q, Lu, Z & Xu, D 2023, 'Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function', Nature cell biology, vol. 25, no. 5, pp. 714-725. https://doi.org/10.1038/s41556-023-01133-9

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title = "Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function",

abstract = "Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.",

author = "Ke Wu and Meisi Yan and Tong Liu and Zheng Wang and Yuran Duan and Yan Xia and Guimei Ji and Yuli Shen and Lei Wang and Lin Li and Peixiang Zheng and Bofei Dong and Qingang Wu and Liwei Xiao and Xueying Yang and Haochen Shen and Ting Wen and Jingjing Zhang and Jinfeng Yi and Yuhan Deng and Xu Qian and Leina Ma and Jing Fang and Qin Zhou and Zhimin Lu and Daqian Xu",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

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doi = "10.1038/s41556-023-01133-9",

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pages = "714--725",

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AU - Wu, Ke

AU - Yan, Meisi

AU - Liu, Tong

AU - Wang, Zheng

AU - Duan, Yuran

AU - Xia, Yan

AU - Ji, Guimei

AU - Shen, Yuli

AU - Wang, Lei

AU - Li, Lin

AU - Zheng, Peixiang

AU - Dong, Bofei

AU - Wu, Qingang

AU - Xiao, Liwei

AU - Yang, Xueying

AU - Shen, Haochen

AU - Wen, Ting

AU - Zhang, Jingjing

AU - Yi, Jinfeng

AU - Deng, Yuhan

AU - Qian, Xu

AU - Ma, Leina

AU - Fang, Jing

AU - Zhou, Qin

AU - Lu, Zhimin

AU - Xu, Daqian

PY - 2023/5

Y1 - 2023/5

N2 - Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

AB - Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.

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Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function

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