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 [5]. It is involved in multiple cellular processes and signaling pathways, with its functions having implications for various biological and disease-related contexts. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, have been valuable in studying Rab4a.

In lupus-prone mice, deletion of Rab4a in T cells restrains CD98 expression, mitochondrial metabolism, and lineage skewing, attenuating glomerulonephritis. This shows that Rab4a-directed endosome traffic is a multilevel regulator of T cell lineage specification during lupus pathogenesis [1]. In cancer research, suppression of Rab4a in cancer cells abolishes self-renewal and tumor-forming ability. It regulates epithelial-to-mesenchymal transition (EMT) through modulating RAC1 activation and controls cancer cell stemness via the RAB4A-NUMB-NOTCH-SOX2 signaling axis [2,3]. In melanocytes, knockdown of Rab4a results in defective melanosome maturation and mislocalization of melanosomal proteins [4].

In conclusion, Rab4a is essential for endosomal sorting and recycling, and its functions are implicated in diseases like lupus and cancer. Studies using KO/CKO mouse models have provided insights into its role in these disease conditions, highlighting its potential as a therapeutic target.

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. 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/