Atp6v0a1, encoding the a1-subunit of the V0 domain of vacuolar H+-ATPases (V-ATPases), is crucial for proton transport across cellular membranes, acidifying organelles like endosomes and lysosomes. V-ATPases are involved in multiple cellular processes such as autophagy, protein trafficking, and endocytosis [2,3,4].

Homozygous mutant mice harboring human-like Atp6v0a1 variants (Atp6v0a1R741Q and Atp6v0a1A512P) show embryonic lethality and early postnatal mortality respectively. In Atp6v0a1A512P/A512P mice, there are lysosomal dysfunction, cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling, decreased synaptic connectivity, and lowered neurotransmitter contents in synaptic vesicles, demonstrating its essential role in neuronal development [2]. In colorectal cancer cells, ATP6V0A1-dependent cholesterol absorption triggers immunosuppressive signaling. It facilitates cholesterol absorption through RABGEF1-dependent endosome maturation, leading to cholesterol-related immunosuppression by upregulating TGF-β1, which suppresses memory CD8+ T-cell anti-tumor activities. Daclatasvir, an ATP6V0A1 inhibitor, can enhance memory CD8+ T-cell activity and suppress tumor growth [1].

In conclusion, Atp6v0a1 is essential for brain development in terms of neuronal integrity and connectivity. Its role in facilitating cholesterol-mediated immunosuppression in colorectal cancer reveals its significance in cancer-immunity interactions. Gene-knockout mouse models have been instrumental in uncovering these functions, providing insights into neurological disorders and potential immunotherapy targets for colorectal cancer [1,2].

References:

1. Huang, Tu-Xiong, Huang, Hui-Si, Dong, Shao-Wei, Zou, Chang, Fu, Li. 2024. ATP6V0A1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory CD8+ T cells. In Nature communications, 15, 5680. doi:10.1038/s41467-024-50077-7. https://pubmed.ncbi.nlm.nih.gov/38971819/

2. Aoto, Kazushi, Kato, Mitsuhiro, Akita, Tenpei, Matsumoto, Naomichi, Saitsu, Hirotomo. 2021. ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H+-ATPases is essential for brain development in humans and mice. In Nature communications, 12, 2107. doi:10.1038/s41467-021-22389-5. https://pubmed.ncbi.nlm.nih.gov/33833240/

3. Bott, Laura C, Forouhan, Mitra, Lieto, Maria, Wood, Matthew J A, Rinaldi, Carlo. 2021. Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. In Brain communications, 3, fcab245. doi:10.1093/braincomms/fcab245. https://pubmed.ncbi.nlm.nih.gov/34909687/

4. Indrawinata, Karen, Argiropoulos, Peter, Sugita, Shuzo. 2023. Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms. In Frontiers in molecular neuroscience, 16, 1135015. doi:10.3389/fnmol.2023.1135015. https://pubmed.ncbi.nlm.nih.gov/37465367/