TY - JOUR TI - Endoplasmic reticulum-associated SKN-1A/Nrf1 mediates a cytoplasmic unfolded protein response and promotes longevity AU - Lehrbach, Nicolas J AU - Ruvkun, Gary A2 - Ron, David A2 - Struhl, Kevin A2 - Dillin, Andrew VL - 8 PY - 2019 DA - 2019/04/11 SP - e44425 C1 - eLife 2019;8:e44425 DO - 10.7554/eLife.44425 UR - https://doi.org/10.7554/eLife.44425 AB - 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 C. elegans 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. KW - proteasome KW - UPR KW - aging KW - SKN-1 KW - NFE2L1 KW - protein quality control JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -