Extracellular protein aggregation is etiologically responsible for many amyloid disease pathologies. In intracellular environments, organelle-specific stress-signaling pathways respond to the presence of misfolded proteins by inducing chaperone expression to restore proteostasis. In contrast, extracellular environments such as the blood must rely on protein secretion from cells to provide their proteome and do not have a defined mechanism to restore proteostasis in response to stress. Because misfolding-prone proteins that reach the extracellular space typically originate in the endoplasmic reticulum (ER), we hypothesized that the Unfolded Protein Response (UPR), the signaling pathway that enhances ER proteostasis in response to misfolded protein in the ER, might also induce chaperone secretion to enhance extracellular proteostasis. We identified and validated the ER Hsp40 ERdj3 as a UPR-regulated secreted chaperone, both in cell culture and in living mice. Secreted ERdj3 binds misfolded proteins in the extracellular space and substoichiometrically inhibits protein aggregation, consistent with a holdase chaperone activity. ERdj3 also attenuates proteotoxicity of disease-associated toxic prion protein, demonstrating that it can functionally enhance extracellular proteostasis. Under conditions where ER chaperoning capacity through the Hsp70 cycle is overwhelmed, ERdj3 can co-secrete with destabilized, aggregation-prone proteins in a stable complex. This novel mechanism preemptively provides extracellular chaperoning of proteotoxic misfolded proteins that evade ER quality control, and directly links ER and extracellular proteostasis. In summary, we find that ERdj3 secretion provides a mechanism for the UPR to enhance extracellular proteostasis in response to threats originating in the early secretory pathway.

Enhancing extracellular proteostasis through the unfolded protein response

249th National Meeting (2015)

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