Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity.

Unfolded protein responses (UPRs) safeguard cellular function during proteotoxic stress and aging. In a previous paper (Lehrbach and Ruvkun, 2016) we showed that the ER-associated SKN-1A/Nrf1 transcription factor activates proteasome subunit expression in response to proteasome dysfunction, but it was not established whether SKN-1A/Nrf1 adjusts proteasome capacity in response to other proteotoxic insults. Here, we reveal that misfolded endogenous proteins and the human amyloid beta peptide trigger activation of proteasome subunit expression by SKN-1A/Nrf1. SKN-1A activation is protective against age-dependent defects caused by accumulation of misfolded and aggregation-prone proteins. In a Alzheimer's disease model, SKN-1A/Nrf1 slows accumulation of the amyloid beta peptide and delays adult-onset cellular dysfunction. Our results indicate that SKN-1A surveys cellular protein folding and adjusts proteasome capacity to meet the demands of protein quality control pathways, revealing a new arm of the cytosolic UPR. This regulatory axis is critical for healthy aging and may be a target for therapeutic modulation of human aging and age-related disease.