XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity

Cell. 2013 Jun 20;153(7):1435-47. doi: 10.1016/j.cell.2013.05.042.

Abstract

The ability to ensure proteostasis is critical for maintaining proper cell function and organismal viability but is mitigated by aging. We analyzed the role of the endoplasmic reticulum unfolded protein response (UPR(ER)) in aging of C. elegans and found that age-onset loss of ER proteostasis could be reversed by expression of a constitutively active form of XBP-1, XBP-1s. Neuronally derived XBP-1s was sufficient to rescue stress resistance, increase longevity, and activate the UPR(ER) in distal, non-neuronal cell types through a cell-nonautonomous mechanism. Loss of UPR(ER) signaling components in distal cells blocked cell-nonautonomous signaling from the nervous system, thereby blocking increased longevity of the entire animal. Reduction of small clear vesicle (SCV) release blocked nonautonomous signaling downstream of xbp-1s, suggesting that the release of neurotransmitters is required for this intertissue signaling event. Our findings point toward a secreted ER stress signal (SERSS) that promotes ER stress resistance and longevity.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Caenorhabditis elegans / physiology*
  • Caenorhabditis elegans Proteins / metabolism*
  • Carrier Proteins / metabolism*
  • Endoplasmic Reticulum Stress*
  • Longevity*
  • Neurons / metabolism*
  • Organ Specificity
  • Protein-Serine-Threonine Kinases / metabolism
  • Unfolded Protein Response*

Substances

  • Caenorhabditis elegans Proteins
  • Carrier Proteins
  • XBP-1 protein, C elegans
  • phorbol ester binding protein
  • Protein-Serine-Threonine Kinases
  • IRE-1 protein, C elegans