BAG3-mediated re-routing of protein degradation towards autophagy upon proteasomal impairment

Eukaryotic cells use autophagy and the ubiquitin–proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). How the proteasomal clients are re-routed to the autophagosomal pathway has remained unclear. We found that several stress pathways that are induced upon disturbances in protein homeostasis as well as by direct chemically-induced proteasomal inhibition increase the protein levels of BAG3, a partner of the heat shock proteins HSPB8 and Hsp70. BAG3 induces the sequestration of Hsp70-bound proteasomal clients into cytoplasmic puncta which leads to their re-routing to autophagosomes for degradation. This occurs through competitive inhibition with its family member BAG1, which normally directs Hsp70-bound clients to the proteasome.