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

被引：118
作者：
Zurhove, Kai [1 ,2 ,3 ,4 ]
Nakajima, Chikako [1 ,2 ,3 ,4 ]
Herz, Joachim [3 ,4 ,5 ]
Bock, Hans H. [1 ,2 ,3 ,4 ]
May, Petra [1 ,2 ,3 ,4 ]
机构：
[1] Univ Hosp, Dept Med 2, D-79106 Freiburg, Germany
[2] Univ Freiburg, D-79106 Freiburg, Germany
[3] Univ Hosp, Ctr Neurosci, D-79104 Freiburg, Germany
[4] Univ Freiburg, D-79104 Freiburg, Germany
[5] Univ Texas SW Med Ctr Dallas, Dept Mol Genet, Dallas, TX 75390 USA
来源：
SCIENCE SIGNALING | 2008年 / 1卷 / 47期
关键词：
D O I：
10.1126/scisignal.1164263
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
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页数：12
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