Lifespan extension conferred by endoplasmic reticulum secretory pathway deficiency requires induction of the unfolded protein response

PLoS Genet. 2014 Jan;10(1):e1004019. doi: 10.1371/journal.pgen.1004019. Epub 2014 Jan 2.

Abstract

Cells respond to accumulation of misfolded proteins in the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR) signaling pathway. The UPR restores ER homeostasis by degrading misfolded proteins, inhibiting translation, and increasing expression of chaperones that enhance ER protein folding capacity. Although ER stress and protein aggregation have been implicated in aging, the role of UPR signaling in regulating lifespan remains unknown. Here we show that deletion of several UPR target genes significantly increases replicative lifespan in yeast. This extended lifespan depends on a functional ER stress sensor protein, Ire1p, and is associated with constitutive activation of upstream UPR signaling. We applied ribosome profiling coupled with next generation sequencing to quantitatively examine translational changes associated with increased UPR activity and identified a set of stress response factors up-regulated in the long-lived mutants. Besides known UPR targets, we uncovered up-regulation of components of the cell wall and genes involved in cell wall biogenesis that confer resistance to multiple stresses. These findings demonstrate that the UPR is an important determinant of lifespan that governs ER stress and identify a signaling network that couples stress resistance to longevity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum Stress / genetics*
  • Humans
  • Longevity / genetics*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mutation
  • Protein Folding*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Ribosomes / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Secretory Pathway / genetics
  • Signal Transduction / genetics
  • Unfolded Protein Response / genetics*

Substances

  • Membrane Glycoproteins
  • Saccharomyces cerevisiae Proteins
  • IRE1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases