Gamma-secretase limits the inflammatory response through the processing of LRP1

Sci Signal. 2008 Nov 25;1(47):ra15. doi: 10.1126/scisignal.1164263.

Abstract

Inflammation is a potentially self-destructive process that needs tight control. We have identified a nuclear signaling mechanism through which the low-density lipoprotein receptor-related protein 1 (LRP1) limits transcription of lipopolysaccharide (LPS)-inducible genes. LPS increases the proteolytic processing of the ectodomain of LRP1, which results in the gamma-secretase-dependent release of the LRP1 intracellular domain (ICD) from the plasma membrane and its translocation to the nucleus, where it binds to and represses the interferon-gamma promoter. Basal transcription of LPS target genes and LPS-induced secretion of proinflammatory cytokines are increased in the absence of LRP1. The interaction between LRP1-ICD and interferon regulatory factor 3 (IRF-3) promotes the nuclear export and proteasomal degradation of IRF-3. Feedback inhibition of the inflammatory response through intramembranous processing of LRP1 thus defines a physiological role for gamma-secretase.

MeSH terms

  • Active Transport, Cell Nucleus
  • Amyloid Precursor Protein Secretases / immunology*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Fibroblasts / cytology
  • Inflammation*
  • Interferon Regulatory Factor-3
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism*
  • Mice
  • Proteasome Endopeptidase Complex / metabolism
  • Transcription, Genetic

Substances

  • Interferon Regulatory Factor-3
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Amyloid Precursor Protein Secretases
  • Proteasome Endopeptidase Complex