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

Nicolas J Lehrbach,Gary Ruvkun

doi:10.7554/elife.44425

Abstract

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.

Highlights

Loss of proteostasis and accumulation of damaged and misfolded proteins is a hallmark of aging (Lopez-Otın et al, 2013)
Activation of rpt-3p::gfp in proteasome hypomorphic mutants requires skn-1 and depletion of SKN-1 by RNAi causes larval lethality in all but one of the mutant strains, skn-1 (RNAi) is not larval lethal in wild type (Table 1, Figure 1—figure supplement 1). These data indicate that a wide range of perturbations to proteasome function trigger SKN-1A activation and confirm that compensatory upregulation of proteasome subunit genes by SKN-1A is critical for survival of proteasome dysfunction, either due to mutations or pharmacological inhibition (Keith et al, 2016; Lehrbach and Ruvkun, 2016)
We found that amyloid beta peptide (Ab) expression in muscle triggers strong muscle-specific activation of rpt-3p::gfp, which is lost in skn-1a(mg570) mutant animals that lack the transmembrane-domain-containing Nrf1 orthologue SKN-1A (Figure 1f)

Summary

Introduction

Loss of proteostasis and accumulation of damaged and misfolded proteins is a hallmark of aging (Lopez-Otın et al, 2013). Cells detect protein misfolding and activate unfolded protein responses (UPRs) that adjust protein metabolism to restore proteostasis (Pilla et al, 2017). These changes include inhibition of translation to limit synthesis of new proteins, upregulation of chaperones that mediate protein folding, and enhanced destruction of misfolded proteins via the proteasome or autophagy. Increasing the activity of UPR pathways to enhance proteostasis may be a means to combat these diseases or even aging itself (Powers et al, 2009; Taylor and Dillin, 2011)

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Results

Conclusion