PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress.

ABSTRACT: The PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs secretion of destabilized TTR during thapsigargin (Tg)-induced ER stress by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition increases the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization

SUBMITTER: Romine IC 

PROVIDER: S-EPMC6344643 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature