Figure 7. ERdj3 secretion links ER and extracellular proteostasis environments during conditions of ER stress.

In response to ER stress, newly synthesized ERdj3 binds misfolded ER client proteins and delivers them to BiP for chaperoning in the Hsp70 cycle. When free BiP becomes limiting, or if repeated BiP cycling cannot productively deplete the levels of the misfolded client, the stable ERdj3–client complex is co-secreted to the extracellular environment, preemptively binding the misfolded protein and preventing the aggregation of the misfolded client protein in the extracellular space. Furthermore, stress-induced ERdj3 can be secreted on its own into the extracellular space where it can bind to misfolded, aggregation-prone client proteins and attenuate pathologic protein aggregation in the extracellular environment.