Vapb, short for Vesicle-associated membrane protein-associated protein B, is an ER-anchored protein that plays a crucial role in multiple cellular processes. It mediates tethers between the endoplasmic reticulum (ER) and membranes of other organelles, especially important for the formation and function of mitochondria-associated membranes (MAMs) through its interaction with PTPIP51. MAMs are vital intracellular signaling hubs regulating calcium homeostasis, lipid metabolism, mitochondrial function, and apoptosis [1,3]. Vapb is also involved in insulin/IGF signaling by stabilizing IRS-1 signalosomes through ER-targeting [2].

In a mouse model of cerebral ischemia-reperfusion injury (CIRI), knockdown of VapB led to exacerbated damage to MAMs, excessive autophagy activation, increased reactive oxygen species (ROS) production, an enlarged infarct area, and exacerbated neurological deficits. This was accompanied by the inhibition of the PI3K/AKT/mTOR pathway, suggesting that VapB-PTPIP51 protects against ischemic stroke by inhibiting autophagy activation [3]. In medulloblastoma cells, knockout of VapB (VapBKO) delayed cell cycle progression and decreased the transcript levels of WNT-related proteins, indicating that VapB is required for the proliferation of these cells [4].

In conclusion, VapB is essential for maintaining the structure and function of MAMs, regulating insulin/IGF signaling, and influencing cell proliferation in certain cancers. Studies using knockout mouse models have revealed its significance in ischemic stroke and medulloblastoma, providing potential therapeutic targets for these diseases.

References:

1. Jiang, Tao, Ruan, Nan, Luo, Pengcheng, Liu, Yu, Zhang, Cuntai. 2024. Modulation of ER-mitochondria tethering complex VAPB-PTPIP51: Novel therapeutic targets for aging-associated diseases. In Ageing research reviews, 98, 102320. doi:10.1016/j.arr.2024.102320. https://pubmed.ncbi.nlm.nih.gov/38719161/

2. Gao, Xiu Kui, Sheng, Zu Kang, Lu, Ye Hong, Zheng, Li Ling, Zhou, Yi Ting. 2023. VAPB-mediated ER-targeting stabilizes IRS-1 signalosomes to regulate insulin/IGF signaling. In Cell discovery, 9, 83. doi:10.1038/s41421-023-00576-6. https://pubmed.ncbi.nlm.nih.gov/37528084/

3. Li, Mingyang, Zhang, Yonggang, Yu, Guixiang, Xiong, Xiaoxing, Jian, Zhihong. . Mitochondria-associated endoplasmic reticulum membranes tethering protein VAPB-PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy. In CNS neuroscience & therapeutics, 30, e14707. doi:10.1111/cns.14707. https://pubmed.ncbi.nlm.nih.gov/38584329/

4. Faria Assoni, Amanda, Giove Mitsugi, Thiago, Wardenaar, René, Foijer, Floris, Keith Okamoto, Oswaldo. 2023. Neurodegeneration-associated protein VAPB regulates proliferation in medulloblastoma. In Scientific reports, 13, 19481. doi:10.1038/s41598-023-45319-5. https://pubmed.ncbi.nlm.nih.gov/37945695/