Bag2, short for Bcl2-associated athanogene 2, functions as a co-chaperone. It interacts with the ATPase domain of heat shock protein 70 (dHsp70) via its BAG domain and is involved in various cellular functions such as apoptosis, autophagy, protein folding and homeostasis [1,3]. It participates in multiple pathways, like the regulation of mitophagy through its interaction with Pink1 [2], and the MAPK pathway [5]. It is of great biological importance as its dysregulation is associated with numerous diseases including cancers and neurodegenerative diseases [1]. Genetic models, especially KO/CKO mouse models, can be valuable in studying its function.

In DIC models, both Bag2 knockdown and DOX administration led to apoptosis, mitochondrial dysfunction, and impaired mitophagy, while Bag2 overexpression had protective effects, indicating its role in maintaining Pink1-mediated mitophagy [2]. In breast cancer, silencing BAG2 reduced mutant p53 aggregates and increased chemotherapy sensitivity, showing its role in chemoresistance [4]. In gastric cancer, BAG2 knockdown inhibited cell proliferation, invasion, and migration through the AKT/mTOR and ERK pathways [5].

In conclusion, Bag2 is a crucial co-chaperone involved in multiple cellular processes and disease-related pathways. The use of KO/CKO mouse models and other loss-of-function experiments in DIC, breast cancer, and gastric cancer has revealed its significance in maintaining mitochondrial function, and its role in cancer progression and chemoresistance, providing potential therapeutic targets for these diseases.

References:

1. Qin, Lixia, Guo, Jifeng, Zheng, Qian, Zhang, Hainan. 2016. BAG2 structure, function and involvement in disease. In Cellular & molecular biology letters, 21, 18. doi:10.1186/s11658-016-0020-2. https://pubmed.ncbi.nlm.nih.gov/28536620/

2. Xiao, Hongkai, Liang, Siyu, Cai, Qinhong, Jin, Liang, Chen, Xiaochao. 2024. Bag2 protects against doxorubicin-induced cardiotoxicity by maintaining Pink1-mediated mitophagy. In Toxicology, 509, 153980. doi:10.1016/j.tox.2024.153980. https://pubmed.ncbi.nlm.nih.gov/39442788/

3. Hou, Mengwen, Yue, Man, Han, Xu, Tu, Mengjie, An, Yang. 2024. Comparative analysis of BAG1 and BAG2: Insights into their structures, functions and implications in disease pathogenesis. In International immunopharmacology, 143, 113369. doi:10.1016/j.intimp.2024.113369. https://pubmed.ncbi.nlm.nih.gov/39405938/

4. Huang, Xinjian, Shi, Dongni, Zou, Xuxiazi, Jian, Yunting, Lin, Chuyong. 2023. BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate. In Theranostics, 13, 339-354. doi:10.7150/thno.78492. https://pubmed.ncbi.nlm.nih.gov/36593950/

5. Sun, Lisha, Chen, Guanglei, Sun, Anqi, Liu, Caigang, Li, Kai. 2020. BAG2 Promotes Proliferation and Metastasis of Gastric Cancer via ERK1/2 Signaling and Partially Regulated by miR186. In Frontiers in oncology, 10, 31. doi:10.3389/fonc.2020.00031. https://pubmed.ncbi.nlm.nih.gov/32082999/