Cerk-KO Mouse

Ceramide kinase (CERK) is a mammalian lipid kinase responsible for phosphorylating ceramide to produce ceramide-1-phosphate (C1P) [3,4]. C1P is involved in membrane biology, regulation of membrane-bound proteins, and acts as a signaling entity. The CERK-C1P axis is part of the sphingolipid pathway, which is crucial for various cellular functions such as cell signaling, metabolism, growth, and death [4]. Genetic models, like gene knockout mouse models, are valuable for studying CERK.

In a CERK-knockout mouse model, inhibition of CERK exacerbated high-altitude pulmonary edema (HAPE) induced by a hypobaric hypoxic environment. CERK-derived C1P protected against HAPE by stabilizing circadian rhythms and maintaining mitochondrial dynamics. Specifically, CERK inhibition induced aryl hydrocarbon receptor nuclear translocator-like (ARNTL) autophagic degradation, triggering mitochondrial damage, while exogenous C1P prevented ARNTL degradation and alleviated HAPE [1]. In mutant KRAS non-small cell lung cancer (NSCLC), inhibition of CERK induced ferroptosis, reduced cell survival, and synergized with cisplatin in reducing in vivo tumor growth by dysregulating VDAC-mediated mitochondria function [2].

In conclusion, CERK, through the production of C1P, plays essential roles in maintaining mitochondrial dynamics, circadian rhythms, and redox homeostasis. CERK-KO mouse models have revealed its significance in diseases such as HAPE and NSCLC, highlighting its potential as a therapeutic target for these and potentially other related disease conditions.

References:

1. Tian, Liuyang, Zhao, Chenghui, Yan, Yan, He, Kunlun, Zhao, Xiaojing. 2023. Ceramide-1-phosphate alleviates high-altitude pulmonary edema by stabilizing circadian ARNTL-mediated mitochondrial dynamics. In Journal of advanced research, 60, 75-92. doi:10.1016/j.jare.2023.07.008. https://pubmed.ncbi.nlm.nih.gov/37479181/

2. Vu, Ngoc T, Kim, Minjung, Stephenson, Daniel J, MacKnight, H Patrick, Chalfant, Charles E. . Ceramide Kinase Inhibition Drives Ferroptosis and Sensitivity to Cisplatin in Mutant KRAS Lung Cancer by Dysregulating VDAC-Mediated Mitochondria Function. In Molecular cancer research : MCR, 20, 1429-1442. doi:10.1158/1541-7786.MCR-22-0085. https://pubmed.ncbi.nlm.nih.gov/35560154/

3. Dong, Wei, Li, Qing, Lu, Xing, Zhang, Chong, Jin, Junfei. 2024. Ceramide kinase-mediated C1P metabolism attenuates acute liver injury by inhibiting the interaction between KEAP1 and NRF2. In Experimental & molecular medicine, 56, 946-958. doi:10.1038/s12276-024-01203-4. https://pubmed.ncbi.nlm.nih.gov/38556546/

4. Bornancin, Frédéric. 2010. Ceramide kinase: the first decade. In Cellular signalling, 23, 999-1008. doi:10.1016/j.cellsig.2010.11.012. https://pubmed.ncbi.nlm.nih.gov/21111813/