Figure 4.

Model for Hsp70-Bag3-HRI

In resting state, Hsp70 holds the HRI with help of Bag3 and keeps it in inactive form. Further, after sensing proteotoxicity due to (1) disruption of complex Hsp70-Bag3 in presence of JG-98 or (2) in presence of MG-132 after inhibition of proteasome, HRI becomes active and (3) Bag3-HRI complex plays as key role to phosphorylate eIF2a. Further, this cascade of events leads to (4) selective translation of ATF4, followed by transcription of DDIT3(CHOP) leading to apoptosis. Separately, this complex (Bag3-HRI) is degraded through (5) autophagy. In another scenario, in case of (6) Bag3 depletion, accumulation of inactive form of HRI takes place in the system due to inhibition of (7) Bag3-mediated autophagic degradation.