Atp6v0d2, a subunit of the vacuolar ATPase (V-ATPase), is highly expressed in macrophages. It is involved in multiple biological functions such as facilitating autophagosome-lysosome fusion, regulating cholesterol homeostasis, and participating in proton transport-related processes. These functions are associated with pathways like the mTORC1-TFEB axis, and are crucial for maintaining macrophage organelle homeostasis, tissue homeostasis, and overall biological balance. Genetic models, like knockout mice, have been instrumental in studying its functions [1,3,5,6].

In Atp6v0d2 -/- mice, there is enhanced susceptibility to tumor growth, with increased HIF-2α-mediated VEGF production in macrophages, indicating a protumoral phenotype [1]. Atp6v0d2-deficient macrophages show augmented mitochondrial damage, enhanced inflammasome activation, and reduced clearance of Salmonella typhimurium, and Atp6v0d2 knockout mice are more susceptible to DSS-induced colitis and Salmonella typhimurium-induced death [3]. In the context of antiviral innate immunity, virus-infected macrophages with suppressed serine metabolism show increased Atp6v0d2 expression, which promotes YAP lysosomal degradation to enhance IFN-β production [2]. In clear cell renal cell carcinoma, upregulation of Atp6v0d2 by atractylenolide I promotes autophagic degradation of EPAS1/HIF2α, inhibiting angiogenesis and reversing sunitinib resistance [4].

In conclusion, Atp6v0d2 plays essential roles in maintaining macrophage function, and its deficiency can lead to various disease-related phenotypes. Studies using Atp6v0d2 knockout mouse models have revealed its significance in tumor progression, antiviral immunity, bacterial infection, and colitis, highlighting its potential as a therapeutic target in these disease areas [1-4].

References:

1. Liu, Na, Luo, Jing, Kuang, Dong, Wang, Guoping, Yang, Xiang-Ping. 2019. Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2α-mediated tumor progression. In The Journal of clinical investigation, 129, 631-646. doi:10.1172/JCI123027. https://pubmed.ncbi.nlm.nih.gov/30431439/

2. Shen, Long, Hu, Penghui, Zhang, Yanan, Wang, Ting, Yu, Qiujing. 2021. Serine metabolism antagonizes antiviral innate immunity by preventing ATP6V0d2-mediated YAP lysosomal degradation. In Cell metabolism, 33, 971-987.e6. doi:10.1016/j.cmet.2021.03.006. https://pubmed.ncbi.nlm.nih.gov/33798471/

3. Xia, Yu, Liu, Na, Xie, Xiuxiu, Laurence, Arian, Yang, Xiang-Ping. 2019. The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion. In Autophagy, 15, 960-975. doi:10.1080/15548627.2019.1569916. https://pubmed.ncbi.nlm.nih.gov/30681394/

4. Li, Qinyu, Zeng, Kai, Chen, Qian, Yuan, Xianglin, Liu, Bo. 2024. Atractylenolide I inhibits angiogenesis and reverses sunitinib resistance in clear cell renal cell carcinoma through ATP6V0D2-mediated autophagic degradation of EPAS1/HIF2α. In Autophagy, 21, 619-638. doi:10.1080/15548627.2024.2421699. https://pubmed.ncbi.nlm.nih.gov/39477683/

5. Pessoa, Carina Carraro, Reis, Luiza Campos, Ramos-Sanchez, Eduardo Milton, Mortara, Renato Arruda, Real, Fernando. 2019. ATP6V0d2 controls Leishmania parasitophorous vacuole biogenesis via cholesterol homeostasis. In PLoS pathogens, 15, e1007834. doi:10.1371/journal.ppat.1007834. https://pubmed.ncbi.nlm.nih.gov/31199856/

6. Shin, Yoon Kyung, Jo, Young Rae, Lee, Seoung Hoon, Park, Hwan Tae, Shin, Jung Eun. 2023. Regulation of the V-ATPase subunit ATP6V0D2 and its role in demyelination after peripheral nerve injury. In Biochemical and biophysical research communications, 646, 1-7. doi:10.1016/j.bbrc.2023.01.039. https://pubmed.ncbi.nlm.nih.gov/36689911/