There are a number of different pathways that cells can activate to relieve proteotoxic stress caused by the build-up of aberrant proteins, such as autophagy or aggresome formation, or pathways that can regulate programmed cell death. Previously, the authors demonstrated that a protein complex composed of heat-shock protein Hsp70 and co-chaperone Bag3 (the HB complex) integrates proteotoxicity signals and transmits that information to downstream signalling pathways, such as the Hippo pathway. Now, Michael Sherman and colleagues (Baldan et al., 2021) investigate the mechanisms by which the HB complex regulates the Hippo pathway in response to proteotoxic stress. LATS1 is a major effector kinase of the Hippo pathway and directly interacts with Bag3 in the HB complex, so the authors study how Bag3 activity regulates LATS1, which then regulates its downstream transcription factor target YAP. They find that in naïve cells, the HB complex can bind LATS1, YAP and the scaffold protein Amotl2, which links LATS1 and YAP. Under proteotoxic stress, however, Amotl2 dissociates from the complex, preventing phosphorylation of YAP by LATS1 and leading to the nuclear translocation of YAP, which is crucial for its transcriptional function, together with Bag3. Furthermore, in the absence of proteotoxic stress, Bag3 depletion leads to reduced YAP nuclear accumulation. Finally, the authors demonstrate that Bag3 regulates YAP nuclear translocation in response to low cell density, suggesting that the regulatory role of Bag3 is not limited to proteotoxicity. These data demonstrate that Bag3 has a dual function, promoting both YAP cytoplasmic retention in complex with LATS1 and Amotl2, and YAP nuclear translocation.
