脑膜瘤是最常见的原发性颅内肿瘤，占所有神经系统肿瘤的近30%。大约一半的脑膜瘤患者表现出神经纤维蛋白 2 (NF2) 基因失活。在此，NF2 与高级恶性脑膜瘤细胞系 IOMM-Lee 中的内质网 (ER) 钙 (Ca2+) 通道肌醇 1,4,5-三磷酸受体 1 (IP3R1) 和 F1 子域相互作用NF2 在这种相互作用中起着至关重要的作用。功能测定表明，NF2 通过与 IP3R1 结合促进 IP3R (Ser 1756) 的磷酸化和 IP3R 介导的内质网 (ER) Ca2 释放，从而导致 Ca2 依赖性细胞凋亡。 NF2 的敲除减少了 Ca2 的释放并促进了对细胞凋亡的抵抗，野生型 NF2 过表达可以挽救这种情况，但 F1 亚结构域缺失截断过表达则不能挽救这种情况。在小鼠模型中进一步研究了 NF2 缺陷对肿瘤发展的影响。 NF2基因敲除或突变引起的NF2表达水平降低，影响IP3R通道的活性，从而减少Ca2+依赖性细胞凋亡，从而促进肿瘤的发生发展。我们阐明了NF2和IP3R1的相互作用模式，揭示了NF2调节IP3R1介导的Ca2+释放的分子机制，并阐明了脑膜瘤相关NF2变异体的新的致病机制。我们的研究拓宽了目前对 NF2 生物学功能的理解，并为 NF2 相关脑膜瘤的药物筛选提供了思路。© 2024 作者。 FASEB 期刊由 Wiley periodicals LLC 代表美国实验生物学学会联合会出版。

Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.