BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

A number of studies in tumor cell lines of different origin have shown that bag3 silencing or hyperexpression results in, respectively, enhancing or inhibiting spontaneous or drug-induced apoptosis. 9, 24, 25, 30, 31, 34, 36, 37, 44, 49 Furthermore, caspases trigger BAG3 cleavage, thereby facilitating the apoptotic process. 52, 62 BAG3 seems to influence cell survival by interacting with different molecular partner, thus activating multiple pathways. A first demonstrated mechanism of BAG3 anti-apoptotic activity is mediated by its role, as a co-chaperone, in protein delivery to the proteasome. Indeed, although another member of BAG family, that is, BAG1, positively cooperates with Hsp70 and CHIP (C-terminus of the Hsc70-interacting protein) to direct, through its ubiquitin-like domain (Figure 1 ), client proteins to proteasome, 63 BAG3 can interfere with this process by competing with BAG1. 2, 4, 29, 52 Indeed, in osteosarcoma and melanoma cells, BAG3 protects IKK-g from proteasome delivery and this results in sustained NF-kB activation and cell survival. 37 A different mechanism has been observed in glioblastoma cells, in which BAG3 retains BAX protein in the cytosol, preventing its mitochondrial translocation. 36 Both mechanisms rely on an interaction between BAG3 and Hsp70. 36, 37 We can speculate that through its binding to Hsp70, BAG3 might also positively or negatively modulate folding of other apoptosis-regulating proteins, and expect that future research will disclose a very complex regulative mechanism mediated by this protein. More over, as HSP70 can bind to AU-rich elements in the 3 0 -untranslated regions, regulating expression of a number of proteins, including the well-known pro-apoptotic, BH3 only protein Bim, 64 BAG3 might be expected to regulate Hsp70 ability to stabilize Bim mRNA and possibly other mRNAs, involved in various cell functions. Finally, we can envisage functions of BAG3 that are independent of Hsp70, as it could also bind some client proteins through its WW or PXXP domain, directly influencing their stability, localization or activity (Figure 2 ). It is likely that the availability of the different partners underlies the different mechanisms through which BAG3 exerts its anti-apoptotic activity in different cell types.