RBCK1, also known as RANBP2-type and C3HC4-type zinc finger-containing 1, is an E3 ubiquitin ligase. It is a subunit of the linear ubiquitin chain assembly complex and is involved in multiple signaling pathways such as NF-κB signaling [3]. Its abnormal expression has been associated with various biological processes and diseases, indicating its biological importance. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In HFpEF, lovastatin-induced upregulation of circRNA-RBCK1, co-transcribed with the RBCK1 gene, improves diastolic function in male mice. This effect is abolished by loss of function of endothelial AP-2α or circRNA-RBCK1, suggesting a role of the AP-2α/circRNA-RBCK1 signaling in suppressing miR-133a and preventing diastolic dysfunction [1]. In pancreatic cancer, depletion or knockdown of RBCK1 in PDAC cells increases their vulnerability to ferroptotic death both in vitro and in a mouse xenograft model. Mechanistically, RBCK1 interacts with and polyubiquitylates MFN2 to facilitate its proteasomal degradation, leading to decreased mitochondrial ROS production and lipid peroxidation [2].

In summary, RBCK1 plays diverse roles in different biological processes and diseases. In HFpEF, it is involved in the regulation of diastolic function through the AP-2α/circRNA-RBCK1/miR-133a axis. In pancreatic cancer, it confers ferroptosis resistance by facilitating MFN2 degradation. Studies using KO/CKO mouse models have been crucial in uncovering these roles, providing insights into the molecular mechanisms underlying these disease conditions and potential therapeutic targets.

References:

1. Li, Bin, Bai, Wen-Wu, Guo, Tao, Li, Peng, Wang, Shuang-Xi. 2024. Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1. In Nature communications, 15, 2953. doi:10.1038/s41467-024-47327-z. https://pubmed.ncbi.nlm.nih.gov/38580662/

2. Su, Dan, Ding, Chen, Wang, Ruobing, Yang, Gang, Zhang, Taiping. 2024. E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation. In Free radical biology & medicine, 221, 136-154. doi:10.1016/j.freeradbiomed.2024.05.031. https://pubmed.ncbi.nlm.nih.gov/38763208/

3. Chen, Xijun, Ye, Qing, Zhao, Wenxiu, Xie, Chengrong, Wang, Xiaomin. 2022. RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31. In Cell death discovery, 8, 334. doi:10.1038/s41420-022-01126-x. https://pubmed.ncbi.nlm.nih.gov/35869046/