Rab4a, a member of the Ras superfamily of small GTPases, is associated with early endosomes and plays a crucial role in membrane trafficking, specifically in sorting and recycling processes [6]. It is involved in various cellular pathways, influencing cell junction dynamics, endosomal cargo sorting, and receptor recycling, which are essential for maintaining normal cellular functions [4,5]. Genetic models, such as gene knockout, are valuable tools for studying its functions.

In lupus-prone mice, Rab4A deletion in T cells restrains CD98 expression, mitochondrial metabolism, and lineage skewing, attenuating glomerulonephritis. This reveals that Rab4A-directed endosome traffic is a multilevel regulator of T cell lineage specification during lupus pathogenesis [1]. In cancer research, knockdown of RAB4A in vitro and in vivo abolishes cancer cells' self-renewal and tumor-forming ability, highlighting its importance in epithelial-to-mesenchymal transition (EMT), cancer cell stemness, and progression [2,3].

In conclusion, Rab4a is essential for endosomal sorting and recycling, and its functions are crucial in processes like T cell lineage development in lupus and cancer progression. The gene knockout models have significantly contributed to understanding its role in these disease areas, providing potential targets for therapeutic interventions.

References:

1. Huang, Nick, Winans, Thomas, Wyman, Brandon, Banki, Katalin, Perl, Andras. 2024. Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation. In Nature communications, 15, 2598. doi:10.1038/s41467-024-46441-2. https://pubmed.ncbi.nlm.nih.gov/38519468/

2. Karthikeyan, Subbulakshmi, Casey, Patrick J, Wang, Mei. 2022. RAB4A GTPase regulates epithelial-to-mesenchymal transition by modulating RAC1 activation. In Breast cancer research : BCR, 24, 72. doi:10.1186/s13058-022-01564-6. https://pubmed.ncbi.nlm.nih.gov/36307864/

3. Karthikeyan, Subbulakshmi, Casey, Patrick J, Wang, Mei. 2024. RAB4A is a master regulator of cancer cell stemness upstream of NUMB-NOTCH signaling. In Cell death & disease, 15, 778. doi:10.1038/s41419-024-07172-w. https://pubmed.ncbi.nlm.nih.gov/39463384/

4. Nag, Sudeshna, Rani, Shikha, Mahanty, Sarmistha, Raposo, Graca, Setty, Subba Rao Gangi. 2018. Rab4A organizes endosomal domains for sorting cargo to lysosome-related organelles. In Journal of cell science, 131, . doi:10.1242/jcs.216226. https://pubmed.ncbi.nlm.nih.gov/30154210/

5. Mruk, Dolores D, Lau, Ann S N, Sarkar, Oli, Xia, Weiliang. 2007. Rab4A GTPase catenin interactions are involved in cell junction dynamics in the testis. In Journal of andrology, 28, 742-54. doi:. https://pubmed.ncbi.nlm.nih.gov/17494101/

6. Wang, Rui, Shen, Qing. 2024. Generation of RAB4A homozygous knockout induced pluripotent stem cell (iPSC) line. In Stem cell research, 81, 103556. doi:10.1016/j.scr.2024.103556. https://pubmed.ncbi.nlm.nih.gov/39299131/