Fbxo15, also known as Fbx15, is an F-box protein in the ubiquitin E3 ligase complex, Skp1-Cullin1-FBXO15 (SCF(Fbx15)) [1]. It plays crucial roles in multiple biological pathways, such as regulating protein degradation through the ubiquitin-proteasome pathway, which is essential for maintaining normal cellular function.

In cancer cells, FBXO15 knockdown increased P-glycoprotein (P-gp)/ABCB1 expression without affecting its mRNA level, enhancing vincristine resistance and lowering intracellular rhodamine 123 levels, suggesting it regulates P-gp expression through the ubiquitin-proteasome pathway [1]. In mouse embryonic stem cells, Fbxo15 is transcriptionally controlled by pluripotency core factors. Defects in KBP degradation due to Fbxo15-related issues result in unscheduled mitochondrial biogenesis, enhanced respiration, ROS production, and inhibited cell proliferation [2]. In CLP mice, oroxylin A induces the transcription of Fbxo15, and activated FBXO15 protein binds to CHOP, mediating its degradation through the proteasome pathway to relieve immunoparalysis [3]. In pneumonia, S. aureus activates Fbxo15 to mediate proteasomal degradation of cardiolipin synthase 1, disrupting mitochondrial function [4]. Gastrodin reduces Aβ brain levels in an Alzheimer's disease mouse model by inhibiting the binding of FBXO15 to P-gp, thus inhibiting P-gp ubiquitination [5].

In summary, Fbxo15 is essential for regulating protein degradation via the ubiquitin-proteasome pathway, which impacts various biological processes. Its study using gene knockout or other functional studies in mouse models has revealed its significance in cancer drug resistance, mitochondrial biogenesis in stem cells, sepsis-related immunoparalysis, mitochondrial function in pneumonia, and Alzheimer's disease-related Aβ regulation. These findings provide insights into disease mechanisms and potential therapeutic targets.

References:

1. Katayama, Kazuhiro, Noguchi, Kohji, Sugimoto, Yoshikazu. 2013. FBXO15 regulates P-glycoprotein/ABCB1 expression through the ubiquitin--proteasome pathway in cancer cells. In Cancer science, 104, 694-702. doi:10.1111/cas.12145. https://pubmed.ncbi.nlm.nih.gov/23465077/

2. Donato, Valerio, Bonora, Massimo, Simoneschi, Daniele, Pinton, Paolo, Pagano, Michele. 2017. The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells. In Nature cell biology, 19, 341-351. doi:10.1038/ncb3491. https://pubmed.ncbi.nlm.nih.gov/28319092/

3. Zhang, Zhaoxin, Wang, Yun, Shan, Yating, Zhou, Ri, Yin, Wu. 2020. Oroxylin A alleviates immunoparalysis of CLP mice by degrading CHOP through interacting with FBXO15. In Scientific reports, 10, 19272. doi:10.1038/s41598-020-76285-x. https://pubmed.ncbi.nlm.nih.gov/33159144/

4. Chen, Bill B, Coon, Tiffany A, Glasser, Jennifer R, Kagan, Valerian E, Mallampalli, Rama K. 2014. E3 ligase subunit Fbxo15 and PINK1 kinase regulate cardiolipin synthase 1 stability and mitochondrial function in pneumonia. In Cell reports, 7, 476-487. doi:10.1016/j.celrep.2014.02.048. https://pubmed.ncbi.nlm.nih.gov/24703837/

5. Zhu, Chenghao, Wang, Shangtao, Ma, Siyu, Zhang, Wei, Sun, Zhirong. 2024. Gastrodin reduces Aβ brain levels in an Alzheimer's disease mouse model by inhibiting P-glycoprotein ubiquitination. In Phytomedicine : international journal of phytotherapy and phytopharmacology, 135, 156229. doi:10.1016/j.phymed.2024.156229. https://pubmed.ncbi.nlm.nih.gov/39541666/