Subcellular distribution affects BAG1 function.

BAG1 is a potent neuroprotectant as well as a marker of differentiation in neuronal cells. It is known that BAG1 mainly localizes to the nucleus during neuronal development, whereas BAG1 shifts to the cytosol upon neuronal differentiation suggesting that distinct BAG1 functions depend on its subcellular localization. Here, we show that forced BAG1 expression within the nucleus when compared to full-length BAG1 expression and to control cells completely abolishes the neuroprotective effects of BAG1 supporting the notion that cytosolic interaction with Hsp70 is mandatory for BAG1 mediated neuroprotection. At the same time, we observed that cells can no longer differentiate into post-mitotic neurons when BAG1 is only present in the nucleus. In addition, phospho-Erk levels are decreased in those cells indicating that BAG1 has to translocate to the cytosol for Raf-dependent MAPK activation.