Regulation of Extracellular Chaperone Capacity by the Unfolded Protein Response

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DESCRIPTION (provided by applicant): Extracellular protein aggregation is inextricably linked to human neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease and the transthyretin amyloidoses. The importance of protein aggregation in these disorders has led to significant experimental effort focused on characterizing the cellular pathways that regulate extracellular protein homeostasis (or proteostasis). Two primary determinants in defining extracellular proteostasis identified through these efforts are the efficiency of endoplasmic reticulum (ER) quality control pathways and the spectrum and activity of extracellular chaperones. A primary function of the ER is to facilitate the proper folding of proteins for trafficking to downstream environments of the secretory pathway such as the extracellular environment, while preventing the secretion of destabilized, misfolding-prone proteins. Through this so-called quality control mechanism, the ER indirectly influences extracellular proteostasis by reducing the extracellular population of misfolding prone proteins available for concentration- dependent aggregation. Alternatively, extracellular chaperones such as clusterin directly influence extracellular proteostasis by binding misfolding prone proteins, preventing their aggregation. While the combined activity of ER quality control pathways and extracellular chaperones efficiently regulate extracellular proteostasis under normal conditions, imbalances in ER quality control efficiency induced by environmental, genetic or aging- related insults can lead to increased secretion of aggregation-prone proteins that challenge extracellular chaperoning capacity. To confront this challenge, cells activate the unfolded protein response (UPR) - a stress-responsive signaling pathway that translationally and transcriptionally remodels ER quality control pathways. Thus, UPR activation restores ER function and attenuates the secretion of aggregation-prone proteins. Despite the importance of the UPR in regulating proteostasis in the ER and downstream environments of the secretory pathway, no link between UPR activation and extracellular chaperoning capacity has been established. We hypothesize that UPR activation, in response to stress, increases secretion of extracellular chaperones to prevent the aberrant, extracellular aggregation of misfolding prone proteins. Herein, we identify ERdj3 (DNAJB11) as a previously uncharacterized, UPR-regulated extracellular chaperone. We propose to evaluate the capacity for ERdj3 to attenuate pathologic protein aggregation in the extracellular environment, characterize the biological pathways responsible for stress-induced ERdj3 secretion, and identify the subset of secreted proteins that interacts with ERdj3 during normal physiology and in response to stress. Experimental success herein will provide proof-of-principle of a direct, functional role for the UPR in regulating extracellular proteostasis capacit, catalyzing research to both identify other UPR-regulated extracellular proteostasis factors and explore the potential for inducing the UPR-dependent increase in extracellular chaperone capacity to treat aggregation-associated degenerative disorders.