Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling

Nat Cell Biol. 2009 Dec;11(12):1473-80. doi: 10.1038/ncb1996. Epub 2009 Oct 25.


The endoplasmic reticulum (ER) unfolded protein response (UPR) restores equilibrium to the ER, but prolonged expression of the UPR effector CHOP (GADD153) is cytotoxic. We found that CHOP expression induced by ER stress was suppressed by prior engagement of toll-like receptor (TLR) 3 or 4 through a TRIF-dependent pathway. TLR engagement did not suppress phosphorylation of PERK or eIF-2alpha, which are upstream of CHOP, but phospho-eIF-2alpha failed to promote translation of the CHOP activator ATF4. In mice subjected to systemic ER stress, pretreatment with low dose lipopolysaccharide (LPS), a TLR4 ligand, suppressed CHOP expression and apoptosis in splenic macrophages, renal tubule cells and hepatocytes, and prevented renal dysfunction and hepatosteatosis. This protective effect of LPS did not occur in Trif(-/-) mice or in wild-type mice in which CHOP expression was genetically restored. Thus, TRIF-mediated signals from TLRs selectively attenuate translational activation of ATF4 and its downstream target gene CHOP. We speculate that this mechanism evolved to promote survival of TLR-expressing cells that experience prolonged levels of physiological ER stress in the course of the host response to invading pathogens.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Adaptor Proteins, Vesicular Transport / deficiency
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Lipopolysaccharides / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction*
  • Stress, Physiological
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism*
  • Transcription Factor CHOP / deficiency
  • Transcription Factor CHOP / metabolism*
  • Unfolded Protein Response*


  • ATF4 protein, human
  • Adaptor Proteins, Vesicular Transport
  • Atf4 protein, mouse
  • DDIT3 protein, human
  • Ddit3 protein, mouse
  • Lipopolysaccharides
  • TICAM-1 protein, mouse
  • Toll-Like Receptors
  • Activating Transcription Factor 4
  • Transcription Factor CHOP