The UPRER: Sensor and Coordinator of Organismal Homeostasis

Mol Cell. 2017 Jun 15;66(6):761-771. doi: 10.1016/j.molcel.2017.05.031.


Life is stressful. Organisms are repeatedly exposed to stressors that disrupt protein homeostasis (proteostasis), resulting in protein misfolding and aggregation. To sense and respond to proteotoxic perturbations, cells have evolved compartment-specific stress responses, such as the unfolded protein response of the endoplasmic reticulum (UPRER). However, UPRER function is impaired with age, which, we propose, creates a permissive environment for protein aggregation, unresolved ER stress, and chronic inflammation. Understanding age-related changes to the UPRER will provide new avenues for therapeutic intervention in metabolic disease, neurodegeneration, and aging.

Keywords: ER stress; NF-kappaB; XBP1; aging; amyotrophic lateral sclerosis; chronic inflammation; endoplasmic reticulum; metabolic disease; protein aggregation; unfolded protein response.

Publication types

  • Review

MeSH terms

  • Aging / metabolism
  • Aging / pathology
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum Stress*
  • Homeostasis
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation Mediators
  • NF-kappa B / metabolism
  • Protein Aggregates
  • Signal Transduction*
  • Unfolded Protein Response*


  • Inflammation Mediators
  • NF-kappa B
  • Protein Aggregates