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

2008; American Association for the Advancement of Science; Volume: 1; Issue: 47 Linguagem: Inglês

10.1126/scisignal.1164263

1937-9145

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

Protease and Inhibitor Mechanisms

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.