Regulating extracellular proteostasis capacity through the unfolded protein response

Area of Science:

• Cell Biology
• Molecular Biology
• Neuroscience

Background:

• Extracellular protein aggregation into toxic species underlies amyloid diseases.
• Endoplasmic reticulum (ER) stress disrupts protein homeostasis, leading to misfolded protein secretion and aggregation.
• The Unfolded Protein Response (UPR) manages ER proteostasis but its extracellular role is unclear.

Purpose of the Study:

• To investigate the UPR's role in extracellular proteostasis during ER stress.
• To identify mechanisms by which the UPR influences extracellular protein aggregation.
• To explore the function of ERdj3 in maintaining extracellular proteostasis.

Main Methods:

• Investigated UPR-regulated secreted proteins.
• Assessed the impact of ERdj3 on extracellular proteostasis.
• Analyzed mechanisms coordinating intra- and extracellular proteostasis.

Main Results:

• Identified ERdj3 as a UPR-regulated secreted chaperone.
• Demonstrated that ERdj3 enhances extracellular proteostasis capacity under ER stress.
• Revealed a direct UPR pathway influencing extracellular protein aggregation.

Conclusions:

• The UPR directly impacts extracellular proteostasis via secreted factors like ERdj3.
• ERdj3 secretion represents a novel mechanism for managing extracellular protein aggregation during ER stress.
• Understanding ERdj3's role may offer therapeutic strategies for amyloid diseases.