Rab4b, a small GTPase in the RAS superfamily, is involved in multiple essential cellular functions such as endocytic trafficking, endosomal recycling, and the control of glucose transporter GLUT4 trafficking, which are crucial for cell homeostasis, glucose homeostasis, synaptic homeostasis, and adaptive immunity [3,4,6,7,8]. It is also associated with pathways like the insulin and 20-hydroxyecdysone (20E) pathways in insects, regulating glycogen level and metamorphosis [9]. Gene knockout models have been valuable in studying its functions.

In PK-15 cells, Rab4b knockout increased resistance to Glaesserella parasuis cytolethal distending toxin (GpCDT)-induced cytotoxicity, while overexpression enhanced it. GpCDT may bind with Rab4b, and Rab4b is essential for GpCDT to be transported to early endosomes [1]. In T cells, specific depletion of Rab4b led to adipocyte hypertrophy, insulin resistance, and an adipose Treg/Th17 imbalance in mice [3]. Knockout of Rab4b in PK15 cells inhibited Japanese encephalitis virus (JEV) replication, while overexpression promoted it. Rab4b also facilitated JEV adsorption, internalization, assembly, and release [2]. In U251 and BV2 cells, RAB4B knockout significantly reduced JEV genome copies and viral titers, which were restored upon re-introduction of RAB4B. RAB4B was shown to be required for JEV internalization into early endosomes, with a direct interaction between RAB4B and the JEV E protein [5].

In conclusion, Rab4b is a key player in multiple biological processes, including endocytic trafficking, viral replication, and cell-cycle-related cytotoxicity. Gene knockout models have been instrumental in revealing its role in diseases related to insulin resistance, viral infections, and bacterial toxin-induced cytotoxicity, providing insights into potential therapeutic targets for these conditions.

References:

1. Zhang, Yiwen, Yang, Zhen, Dai, Ke, Cao, Sanjie, Wen, Yiping. 2024. Rab4b Promotes Cytolethal Distending Toxin from Glaesserella parasuis-Induced Cytotoxicity in PK-15 Cells. In Toxins, 16, . doi:10.3390/toxins16090407. https://pubmed.ncbi.nlm.nih.gov/39330865/

2. Zhao, Qin, Miao, Chang, Chen, Yi-Ting, Zhao, Fei, Cao, San-Jie. 2024. Host Factor Rab4b Promotes Japanese Encephalitis Virus Replication. In Microorganisms, 12, . doi:10.3390/microorganisms12091804. https://pubmed.ncbi.nlm.nih.gov/39338478/

3. Gilleron, Jérôme, Bouget, Gwennaëlle, Ivanov, Stoyan, Tanti, Jean-François, Cormont, Mireille. . Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance. In Cell reports, 25, 3329-3341.e5. doi:10.1016/j.celrep.2018.11.083. https://pubmed.ncbi.nlm.nih.gov/30566860/

4. Gilleron, Jérôme, Chafik, Abderrahman, Lacas-Gervais, Sandra, Tanti, Jean-François, Cormont, Mireille. 2024. Golgi-associated retrograde protein (GARP) complex-dependent endosomes to trans Golgi network retrograde trafficking is controlled by Rab4b. In Cellular & molecular biology letters, 29, 54. doi:10.1186/s11658-024-00574-w. https://pubmed.ncbi.nlm.nih.gov/38627612/

5. Miao, Chang, Zhao, Qin, Zhang, Ya-Ting, Du, Senyan, Cao, San-Jie. 2025. RAB4B and Japanese encephalitis virus E protein interaction is essential for viral entry in early endosomes. In International journal of biological macromolecules, 306, 141452. doi:10.1016/j.ijbiomac.2025.141452. https://pubmed.ncbi.nlm.nih.gov/40020812/

6. Kaddai, Vincent, Gonzalez, Teresa, Keslair, Frédérique, Le Marchand-Brustel, Yannick, Cormont, Mireille. 2009. Rab4b is a small GTPase involved in the control of the glucose transporter GLUT4 localization in adipocyte. In PloS one, 4, e5257. doi:10.1371/journal.pone.0005257. https://pubmed.ncbi.nlm.nih.gov/19590752/

7. Perrin, Laura, Lacas-Gervais, Sandra, Gilleron, Jérôme, Tanti, Jean-François, Cormont, Mireille. 2013. Rab4b controls an early endosome sorting event by interacting with the γ-subunit of the clathrin adaptor complex 1. In Journal of cell science, 126, 4950-62. doi:10.1242/jcs.130575. https://pubmed.ncbi.nlm.nih.gov/24006255/

8. Li, Kezhen, Liang, Shengsheng, Mi, Hua. 2024. Preliminary exploration of the potential biological functions and prognosis values of RAB4B in pan-cancer combing with experimental validation in BLCA. In Translational cancer research, 13, 613-633. doi:10.21037/tcr-23-1840. https://pubmed.ncbi.nlm.nih.gov/38482438/

9. Hou, Li, Cai, Mei-Juan, Liu, Wen, Song, Qian, Zhao, Xiao-Fan. 2012. Small GTPase Rab4b participates in the gene transcription of 20-hydroxyecdysone and insulin pathways to regulate glycogen level and metamorphosis. In Developmental biology, 371, 13-22. doi:10.1016/j.ydbio.2012.06.015. https://pubmed.ncbi.nlm.nih.gov/22824427/