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.
Highlights
Membrane and secretory proteins fold into their native conformations in the endoplasmic reticulum (ER) assisted by chaperones, thiol-disulfide oxidoreductases and other systems supporting protein post-translational control
Accumulation of misfolded proteins in the endoplasmic reticulum, a cellular organelle responsible for protein folding and trafficking, activates protective signaling pathways that restore protein homeostasis. One such conserved signalling pathway is mediated by the protein misfolding sensor Ire1p and the transcription factor Hac1p, which up-regulate endoplasmic reticulum chaperones, oxidative folding components and factors that facilitate degradation of misfolded proteins to alleviate increased protein folding demand
While the loss of Ire1p itself had little effect on lifespan, we found that selective inactivation of the individual protein folding and maturation factors led to increased longevity
Summary
Membrane and secretory proteins fold into their native conformations in the endoplasmic reticulum (ER) assisted by chaperones, thiol-disulfide oxidoreductases and other systems supporting protein post-translational control. The UPR consists of multiple signaling cascades that are activated by three known ER stress sensor proteins, inositol-requiring protein 1 (IRE1), activating transcription factor 6 (ATF6), and double-stranded RNA-activated protein kinase-like ER kinase (PERK) [2,3,4]. Among these signal transducers, only IRE1 is conserved in budding yeast and is solely responsible for the UPR activation in Saccharomyces cerevisiae [5,6]
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