Reversible inhibition of Hsp70 chaperone function by Scythe and Reaper

Protein folding mediated by the Hsp70 family of molecular chaperones requir es both ATP and the co-chaperone Hdj-1. BAG-1 was recently identified as a bcl-2-interacting, anti-apoptotic protein that binds to the ATPase domain o f Hsp70 and prevents the release of the substrate. While this suggested tha t cells had the potential to modulate Hsp70-mediated protein folding, physi ological regulators of BAG-1 have yet to be identified. We report here that the apoptotic regulator Scythe, originally isolated through binding to the potent apoptotic inducer Reaper, shares limited sequence identity with BAG -1 and inhibits Hsp70-mediated protein refolding. Scythe-mediated inhibitio n of Hsp70 is reversed by Reaper, providing evidence for the regulated reve rsible inhibition of chaperone activity. As Scythe functions downstream of Reaper in apoptotic induction, these findings suggest that Scythe/Reaper ma y signal apoptosis, in part through regulating the folding and activity of apoptotic signaling molecules.