Ybx3, also known as DNA-binding protein-A, is a DNA/RNA binding protein belonging to the cold shock protein family. It is involved in multiple essential functions such as gene transcription, DNA repair, cell cycling, translation, and tight junction communication. It has been associated with pathways like PI3K/AKT, cell adhesion molecules, cAMP, calcium, focal adhesion, Ras, Rap1, NF-κB, and Chemokine signaling pathways, playing a crucial role in various biological processes and disease development [1,3]. Genetic models, especially gene knockout (KO) mouse models, have been valuable in studying Ybx3's functions.

In NPC, knockdown of YBX3 by lentivirus shRNA suppressed cell migration in vitro and metastasis in vivo, with YBX3 regulating NPC metastasis through the PI3K/AKT signaling pathway [1]. In BAT, both in vitro loss-and gain-of-function experiments demonstrated YBX3 is essential for brown adipocyte differentiation and thermogenesis. BAT-specific loss of Ybx3 in mice dampened thermogenesis and exacerbated diet-induced obesity [2]. In kidney IRI, genetic deletion of Ybx3 in mice protected from IRI with less immune cell infiltration, endoplasmic reticulum stress and tubular cell damage, by upregulating antioxidant activities and reducing ferroptosis [3]. In BLCa, BLACAT3 recruits YBX3 to shuttle into the nucleus promoting angiogenesis and hematogenous metastasis [4]. In MSCs, circSERPINE2 sequesters YBX3 in the cytoplasm, affecting p21 ubiquitin-mediated degradation and MSC senescence [5]. In ccRCC, high expression of YBX3 was correlated with tumor progression and poor prognosis, and in vitro silencing of YBX3 affected cell proliferation, migration, etc. [6]. In skeletal muscle cells, depletion of YBX3 reduced proliferation and impaired differentiation [7].

In conclusion, Ybx3 plays diverse and significant roles in multiple biological processes and disease conditions. Studies using KO/CKO mouse models have revealed its importance in cancer metastasis (NPC, BLCa, ccRCC), metabolic regulation (BAT thermogenesis), and organ injury protection (kidney IRI), as well as in cell-specific functions like MSC senescence and skeletal muscle cell proliferation and differentiation. Understanding Ybx3's functions through these model-based research provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Fan, Xiaoqin, Xie, Xina, Yang, Ming, Wen, Weiping, Nie, Guohui. 2021. YBX3 Mediates the Metastasis of Nasopharyngeal Carcinoma via PI3K/AKT Signaling. In Frontiers in oncology, 11, 617621. doi:10.3389/fonc.2021.617621. https://pubmed.ncbi.nlm.nih.gov/33816248/

2. Chen, Lin-Yun, Wang, Li-Wen, Wen, Jie, Luo, Xiang-Hang, Feng, Xu. 2024. RNA-binding protein YBX3 promotes PPARγ-SLC3A2 mediated BCAA metabolism fueling brown adipogenesis and thermogenesis. In Molecular metabolism, 90, 102053. doi:10.1016/j.molmet.2024.102053. https://pubmed.ncbi.nlm.nih.gov/39481849/

3. Reichardt, Charlotte, Brandt, Sabine, Bernhardt, Anja, Isermann, Berend, Mertens, Peter R. 2024. DNA-binding protein-A promotes kidney ischemia/reperfusion injury and participates in mitochondrial function. In Kidney international, 106, 241-257. doi:10.1016/j.kint.2024.05.009. https://pubmed.ncbi.nlm.nih.gov/38821446/

4. Xie, Jinbo, Zhang, Hui, Wang, Keyi, Mao, Weipu, Peng, Bo. 2023. M6A-mediated-upregulation of lncRNA BLACAT3 promotes bladder cancer angiogenesis and hematogenous metastasis through YBX3 nuclear shuttling and enhancing NCF2 transcription. In Oncogene, 42, 2956-2970. doi:10.1038/s41388-023-02814-3. https://pubmed.ncbi.nlm.nih.gov/37612524/

5. Chen, Fenglei, Wang, Shan, Zeng, Chenying, Wu, Yanfeng, Shen, Huiyong. 2023. Silencing circSERPINE2 restrains mesenchymal stem cell senescence via the YBX3/PCNA/p21 axis. In Cellular and molecular life sciences : CMLS, 80, 325. doi:10.1007/s00018-023-04975-6. https://pubmed.ncbi.nlm.nih.gov/37831180/

6. Wang, Chen, You, Zhijie, He, Yihui, Chen, Xin. 2023. Identification of RNA-binding protein YBX3 as an oncogene in clear cell renal cell carcinoma. In Functional & integrative genomics, 23, 225. doi:10.1007/s10142-023-01145-6. https://pubmed.ncbi.nlm.nih.gov/37418046/

7. Awad, Silina, Skipper, William, Vostrejs, William, Mehta, Darshan, Cooke, Amy. 2023. The YBX3 RNA-binding protein posttranscriptionally controls SLC1A5 mRNA in proliferating and differentiating skeletal muscle cells. In The Journal of biological chemistry, 300, 105602. doi:10.1016/j.jbc.2023.105602. https://pubmed.ncbi.nlm.nih.gov/38159852/