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ApoER2 processing by presenilin‐1 modulates reelin expression
Author(s) -
Balmaceda Valeria,
CuchilloIbáñez Inmaculada,
Pujadas Liuis,
GarcíaAyllón MaríaSalud,
Saura Carlos A.,
Nimpf Johannes,
Soriano Eduardo,
SáezValero Javier
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-239350
Subject(s) - reelin , low density lipoprotein receptor related protein 8 , dab1 , presenilin , microbiology and biotechnology , chromatin immunoprecipitation , chemistry , receptor , biology , biochemistry , gene expression , gene , medicine , promoter , alzheimer's disease , lipoprotein , disease , very low density lipoprotein , cholesterol
The reelin signaling protein and its downstream components have been associated with synaptic plasticity and neurotransmission. The reelin signaling pathway begins with the binding of reelin to the transmembrane lipoprotein receptor apolipopro‐tein E receptor 2 (ApoER2), which in turns induces the sequential cleavage of ApoER2 by the sequential action of α‐ and γ‐secretases. Using conditional‐knockout mice of the catalytic component of the γ‐secretase complex, presenilin 1 (PS1), we demonstrated increased brain ApoER2 and reelin protein and transcript levels, with no changes in the number of reelin‐positive cells. Using the human SH‐SY5Y neuroblastoma cell line, we showed that ApoER2 processing occurs in the presence of PS1, producing an intracellular ApoER2 C‐terminal fragment. In addition, the pharmacologic inhibition of γ‐secretase in SH‐SY5Y cells led to increased reelin levels. Overexpression of ApoER2 decreased reelin mRNA levels in these cells. A luciferase reporter gene assay and nuclear fractionation confirmed that increased amounts of intracellular fragment of ApoER2 suppressed reelin expression at a transcriptional level. Chromatin immunoprecipitation experiments corroborated that the intracellular fragment of ApoER2 bound to the RELN promoter region. Our study suggests that PS1/γ‐secretase‐dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling.—Balmaceda, V., Cuchillo‐Ibáñez, I., Pujadas, L., García‐Ayllón, M.‐S., Saura, C. A., Nimpf, J., Soriano, E., Sáez‐Valero, J. ApoER2 processing by presenilin‐1 modulates reelin expression. FASEB J. 28, 28–1543 (1554). www.fasebj.org