• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

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

cell biology genetics & genomics proteasome upr aging skn-1 nfe2l1 protein quality control

  • Please log in to reply
No replies to this topic

#1 Engadin

  • Guest
  • 86 posts
  • 214
  • Location:Madrid, Spain.
  • NO

Posted 13 May 2019 - 10:18 AM


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. elegansAlzheimer’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.

 

 

Introduction

 

Loss of proteostasis and accumulation of damaged and misfolded proteins is a hallmark of aging (López-Otín 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. Protein damage that accrues over time appears to eventually overcome these homeostatic mechanisms and contributes to the decline in cellular and organismal health during aging. Mutations that persistently increase production of unfolded proteins or that impair their clearance accelerate this process to cause a number of adult-onset neurodegenerative diseases (Hipp et al., 2014). Conversely, increasing the activity of UPR pathways to enhance proteostasis may be a means to combat these diseases or even aging itself (Powers et al., 2009Taylor and Dillin, 2011).

 

The proteasome mediates the targeted degradation of misfolded and damaged proteins and is essential for proteostasis and cell viability (Collins and Goldberg, 2017). Impaired proteasome function is associated with aging and age-dependent neurodegenerative diseases (Saez and Vilchez, 2014). The SKN-1A/Nrf1 transcription factor regulates the transcription of proteasome subunit genes to increase proteasome biogenesis when the proteasome is inhibited, for example by proteasome inhibitor drugs (Grimberg et al., 2011Lehrbach and Ruvkun, 2016Radhakrishnan et al., 2010Steffen et al., 2010). This compensatory response is essential for the survival of mammalian cells and C. elegans under conditions of impaired proteasome function (Lehrbach and Ruvkun, 2016Radhakrishnan et al., 2010). SKN-1A/Nrf1 is an unusual transcription factor that associates with the ER via an N-terminal transmembrane domain (Glover-Cutter et al., 2013Wang and Chan, 2006). The bulk of SKN-1A/Nrf1 extends into the ER lumen where it undergoes N-linked glycosylation at particular asparagine residues (Radhakrishnan et al., 2014Zhang et al., 2007). After it is glycosylated, SKN-1A/Nrf1 is translocated from the ER lumen to the cytoplasm by the ER-associated degradation (ERAD) machinery, which also targets this short half-life transcription factor for rapid proteasomal degradation (Lehrbach and Ruvkun, 2016Steffen et al., 2010). Under conditions of impaired proteasome function, the SKN-1A/Nrf1 half-life is dramatically increased so that some of the protein escapes degradation and enters the nucleus where it can up-regulate target genes (Lehrbach and Ruvkun, 2016Li et al., 2011Radhakrishnan et al., 2010Steffen et al., 2010). All proteasome subunit genes are direct transcriptional targets of SKN-1A/Nrf1 (Niu et al., 2011Sha and Goldberg, 2014). Activation of SKN-1A/Nrf1 also requires deglycosylation by the peptide N-glycanase PNG-1/NGLY1 and proteolytic cleavage by the aspartic protease DDI-1/DDI2 (Koizumi et al., 2016Lehrbach and Ruvkun, 2016Tomlin et al., 2017). It is not yet known whether the SKN-1A/Nrf1 transcription factor regulates proteasome levels in response to other proteotoxic insults.

 

Here we show that SKN-1A increases proteasome subunit gene expression in response to endogenous misfolded proteins or expression of a foreign aggregation-prone protein, the human amyloid beta peptide. This pathway requires the DDI-1/DDI2 aspartic protease and the PNG-1/NGLY1 peptide N-glycanase, factors that are also required for activation of SKN-1A during proteasome dysfunction. C. elegans mutants that lack SKN-1A show enhanced age-dependent toxicity of misfolding proteins, accelerated tissue degeneration during aging and reduced overall lifespan. Conversely, increasing SKN-1A levels is sufficient to extend C. elegans lifespan. Our data suggests that SKN-1A/Nrf1 mediates an unfolded protein response that adjusts proteasome capacity to ensure protein quality control. This pathway preserves cellular function during aging by limiting accumulation of unfolded and damaged proteins.

 

R E S T   A T   S O U R C E :  eLife







Also tagged with one or more of these keywords: cell biology, genetics & genomics, proteasome, upr, aging, skn-1, nfe2l1, protein quality control

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users