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Sci. Signal., 25 November 2008
Vol. 1, Issue 47, p. ra15
[DOI: 10.1126/scisignal.1164263]

RESEARCH

{gamma}-Secretase Limits the Inflammatory Response Through the Processing of LRP1

Kai Zurhove1,2, Chikako Nakajima1,2, Joachim Herz2,3, Hans H. Bock1,2, and Petra May1,2*

1 Department of Medicine II, University Hospital and University of Freiburg, 79106 Freiburg, Germany.
2 Centre of Neurosciences, University Hospital and University of Freiburg, 79104 Freiburg, Germany.
3 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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.

* To whom correspondence should be addressed. E-mail: Petra.May{at}zfn.uni-freiburg.de

Citation: K. Zurhove, C. Nakajima, J. Herz, H. H. Bock, P. May, {gamma}-Secretase Limits the Inflammatory Response Through the Processing of LRP1. Sci. Signal. 1, ra15 (2008).

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