Research ArticleInflammation

γ-Secretase Limits the Inflammatory Response Through the Processing of LRP1

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Sci. Signal.  25 Nov 2008:
Vol. 1, Issue 47, pp. ra15
DOI: 10.1126/scisignal.1164263

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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 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 γ-secretase.

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