Institute of Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, Germany.
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
Cells. 2020 Nov 4;9(11):2416. doi: 10.3390/cells9112416.
The multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3) represents a key player in the quality control of the cellular proteostasis network. In response to stress BAG3 specifically targets aggregation-prone proteins to the perinuclear aggresome and promotes their degradation via BAG3-mediated selective macroautophagy. To adapt cellular homeostasis to stress, BAG3 modulates and functions in various cellular processes and signaling pathways. Noteworthy, dysfunction and deregulation of BAG3 and its pathway are pathophysiologically linked to myopathies, cancer, and neurodegenerative disorders. Here, we report a BAG3 proteomic signature under proteostasis stress. To elucidate the dynamic and multifunctional action of BAG3 in response to stress, we established BAG3 interactomes under basal and proteostasis stress conditions by employing affinity purification combined with quantitative mass spectrometry. In addition to the identification of novel potential BAG3 interactors, we defined proteins whose interaction with BAG3 was altered upon stress. By functional annotation and protein-protein interaction enrichment analysis of the identified potential BAG3 interactors, we confirmed the multifunctionality of BAG3 and highlighted its crucial role in diverse cellular signaling pathways and processes, ensuring cellular proteostasis and cell viability. These include protein folding and degradation, gene expression, cytoskeleton dynamics (including cell cycle and transport), as well as granulostasis, in particular.
多功能 HSP70 共伴侣 BAG3（BCL-2 相关抗凋亡基因 3）是细胞蛋白质稳态网络质量控制的关键参与者。BAG3 特异性地将易于聚集的蛋白质靶向核周聚集物，并通过 BAG3 介导的选择性巨自噬促进其降解。为了使细胞内稳态适应应激，BAG3 调节和参与多种细胞过程和信号通路。值得注意的是，BAG3 及其途径的功能障碍和失调与肌肉疾病、癌症和神经退行性疾病的病理生理学有关。在这里，我们报告了蛋白质稳态应激下的 BAG3 蛋白质组学特征。为了阐明 BAG3 在应激反应中的动态和多功能作用，我们通过使用亲和纯化结合定量质谱，在基础和蛋白质稳态应激条件下建立了 BAG3 相互作用组。除了鉴定新的潜在 BAG3 相互作用蛋白外，我们还定义了在应激下与 BAG3 相互作用发生改变的蛋白质。通过对鉴定出的潜在 BAG3 相互作用蛋白的功能注释和蛋白质-蛋白质相互作用富集分析，我们证实了 BAG3 的多功能性，并强调了其在多种细胞信号通路和过程中的关键作用，以确保细胞蛋白质稳态和细胞活力。这些包括蛋白质折叠和降解、基因表达、细胞骨架动力学（包括细胞周期和运输）以及特别是粒细胞形成。
