Nrbf2, also known as nuclear receptor binding factor 2, is a regulatory subunit of the ATG14-BECN1/Beclin 1-PIK3C3/VPS34 complex. It positively regulates macroautophagy/autophagy, an essential cellular catabolic process involved in recycling organelles, protein aggregates, and eliminating intracellular pathogens [1,2,3,5,6,7,9,10]. This complex and Nrbf2-mediated autophagy are crucial for maintaining cellular homeostasis and are associated with multiple biological pathways and disease-related processes [1,2,3,4,5,6,7,8,9,10]. Genetic models, such as knockout (KO) mouse models, have been instrumental in studying Nrbf2's functions.

In Nrbf2-deficient mice, much more severe colitis symptoms were observed after administration of dextran sulfate sodium salt (DSS), with prominent intestinal inflammation and apoptotic cell accumulation, indicating Nrbf2 is required for apoptotic cell clearance to restrict intestinal inflammation [1]. In adult neural stem cells (aNSCs), NRBF2 deficiency inhibits the activity of the VPS34 complex, impairs autophagic flux, disrupts the neurogenesis-related protein network, and causes depression-like phenotypes, highlighting its role in preventing chronic stress-induced adult hippocampal neurogenesis (AHN) impairment [2]. In glioblastoma, NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance, and its inhibition by lidoflazine reduces autophagic flux and suppresses IR-induced cell behaviors [3]. In small cell lung cancer (SCLC), NRBF2 positively regulates autophagy, leading to drug resistance, and its MIT domain interacts with the PB1 domain of P62 to regulate the autophagy process [5].

In conclusion, Nrbf2 is essential for autophagy regulation, playing a crucial role in maintaining intestinal homeostasis, preventing chronic stress-induced AHN impairment, regulating glioblastoma radioresistance, and influencing SCLC chemoresistance. KO mouse models have been key in revealing these functions, contributing to our understanding of Nrbf2 in these disease areas.

References:

1. Wu, Ming-Yue, Liu, Le, Wang, Er-Jin, Bian, Zhao-Xiang, Lu, Jia-Hong. 2020. PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation. In Autophagy, 17, 1096-1111. doi:10.1080/15548627.2020.1741332. https://pubmed.ncbi.nlm.nih.gov/32160108/

2. Zhang, Shao-Qi, Deng, Qiao, Zhu, Qi, Wang, Fang, Chen, Jian-Guo. 2023. Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression. In Cell discovery, 9, 90. doi:10.1038/s41421-023-00583-7. https://pubmed.ncbi.nlm.nih.gov/37644025/

3. Kim, Jeongha, Kang, Hyunkoo, Son, Beomseok, Youn, HyeSook, Youn, BuHyun. 2022. NRBF2-mediated autophagy contributes to metabolite replenishment and radioresistance in glioblastoma. In Experimental & molecular medicine, 54, 1872-1885. doi:10.1038/s12276-022-00873-2. https://pubmed.ncbi.nlm.nih.gov/36333468/

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5. Shen, Weitao, Luo, Peng, Sun, Yueqin, Wang, Hai-Hong, Wei, Ting. 2022. NRBF2 regulates the chemoresistance of small cell lung cancer by interacting with the P62 protein in the autophagy process. In iScience, 25, 104471. doi:10.1016/j.isci.2022.104471. https://pubmed.ncbi.nlm.nih.gov/35712081/

6. Cai, Cui-Zan, Yang, Chuanbin, Zhuang, Xu-Xu, Li, Min, Lu, Jia-Hong. 2020. NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation. In Autophagy, 17, 1112-1130. doi:10.1080/15548627.2020.1760623. https://pubmed.ncbi.nlm.nih.gov/32543313/

7. Ohashi, Yohei. 2021. Class III phosphatidylinositol 3-kinase complex I subunit NRBF2/Atg38 - from cell and structural biology to health and disease. In Autophagy, 17, 3897-3907. doi:10.1080/15548627.2021.1872240. https://pubmed.ncbi.nlm.nih.gov/33459128/

8. Wu, Ming-Yue, Cai, Cui-Zan, Yang, Chuanbin, Li, Min, Lu, Jia-Hong. . Emerging roles of NRBF2/PI3KC3 axis in maintaining homeostasis of brain and guts. In Neural regeneration research, 17, 323-324. doi:10.4103/1673-5374.317973. https://pubmed.ncbi.nlm.nih.gov/34269201/

9. Yang, Chuanbin, Cai, Cui-Zan, Song, Ju-Xian, Li, Min, Lu, Jia-Hong. . NRBF2 is involved in the autophagic degradation process of APP-CTFs in Alzheimer disease models. In Autophagy, 13, 2028-2040. doi:10.1080/15548627.2017.1379633. https://pubmed.ncbi.nlm.nih.gov/28980867/

10. Lu, Jiahong, He, Liqiang, Behrends, Christian, Li, Min, Yue, Zhenyu. 2014. NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity. In Nature communications, 5, 3920. doi:10.1038/ncomms4920. https://pubmed.ncbi.nlm.nih.gov/24849286/