期刊
SCIENCE SIGNALING
卷 1, 期 47, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.1164263
关键词
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资金
- NHLBI NIH HHS [R01 HL063762-06, P01 HL020948, R01 HL063762-07, R01 HL063762-02, R37 HL063762, P01 HL020948-250015, R01 HL063762-09, R01 HL063762-10, R01 HL063762-05, P01 HL020948-210015, R01 HL063762-04, R01 HL063762, P01 HL020948-310005, P01 HL020948-320005, R01 HL063762-03, P01 HL020948-240015, R01 HL063762-08, P01 HL020948-230015, R01 HL063762-01, P01 HL020948-220015] Funding Source: Medline
- NINDS NIH HHS [R01 NS043408-03, R01 NS043408-05, R01 NS043408-02, R01 NS043408, R01 NS043408-04, R01 NS043408-01] Funding Source: Medline
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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