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

Kai Zurhove, Chikako Nakajima, Joachim Herz, Hans H. Bock, Petra May

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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 γ-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-γ promoter. Basal transcription of LPS target genes and LPSinduced 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 γ-secretase.

Original languageEnglish (US)
Pages (from-to)ra15
JournalScience signaling
Volume1
Issue number47
DOIs
StatePublished - Nov 25 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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