Gamma-secretase limits the inflammatory response through the processing of LRP1.
Sci Signal
; 1(47): ra15, 2008 Nov 25.
Article
em En
| MEDLINE
| ID: mdl-19036715
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade
/
Secretases da Proteína Precursora do Amiloide
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Inflamação
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article