Gamma-secretase limits the inflammatory response through the processing of LRP1.
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.
Zurhove
Kai
K
Department of Medicine II, University Hospital, University of Freiburg, 79106 Freiburg, Germany.
Nakajima
Chikako
C
Herz
Joachim
J
Bock
Hans H
HH
May
Petra
P
D021581:Active Transport, Cell Nucleus; D053829:Amyloid Precursor Protein Secretases / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D005347:Fibroblasts / Q000166:cytology; D007249:Inflammation; D050838:Interferon Regulatory Factor-3; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014158:Transcription, Genetic
D050838:Interferon Regulatory Factor-3; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex