Figure 3.

Bag6 regulates protein turnover. A: Bag6 regulates the degradation of folding defective nascent polypeptides. Newly synthesized defective polypeptides are detected by Bag6 and ubiquitinated by a yet-to-be identified E3 ubiquitin ligase that interacts with Bag6. Bag6 may escort the substrates to the proteasome for degradation. B: Bag6 assists mislocalized proteins in reaching the proteasome. TA proteins bound by Bag6 can have different fates. Some may be transferred to the downstream ATPase TRC40 for membrane targeting, whereas others are ubiquitinated by Bag6-associated ubiquitin ligases for degradation by the proteasome. Bag6 may function as a timer, analogous to the one in the ER lumen that dictates the degradation of misfolded glycoproteins. For those TA proteins that fail to be efficiently targeted to the membrane, Bag6 would triage them to the degradation pathway. C: Bag6 escorts ERAD substrates to the proteasome in order to enhance degradation efficiency. The recruitment of the Bag6 system to the gp78- and p97-containing retro-translocation complex seems to mark Bag6 as the preferred chaperone that channels dislocated ERAD substrates to the proteasome. Bag6 may interact with the proteasome either directly or via an unknown adaptor indicated by the question mark.