Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein

Presenilin (PS) is essential for the gamma-cleavage required for the generation of the C terminus of amyloid beta-protein (Abeta). However, the mechanism underlying PS-mediated gamma-cleavage remains unclear. We have identified Herp cDNA by our newly developed screening method for the isolation of c...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-04, Vol.277 (15), p.12915-12920
Main Authors: Sai, Xiaorei, Kawamura, Yuuki, Kokame, Koichi, Yamaguchi, Haruyasu, Shiraishi, Hirohisa, Suzuki, Ryo, Suzuki, Toshiharu, Kawaichi, Masashi, Miyata, Toshiyuki, Kitamura, Toshio, De Strooper, Bart, Yanagisawa, Katsuhiko, Komano, Hiroto
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - biosynthesis
Cell Line
Endoplasmic Reticulum - metabolism
Humans
Immunohistochemistry
Membrane Proteins - physiology
Presenilin-1
Presenilin-2
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Summary:Presenilin (PS) is essential for the gamma-cleavage required for the generation of the C terminus of amyloid beta-protein (Abeta). However, the mechanism underlying PS-mediated gamma-cleavage remains unclear. We have identified Herp cDNA by our newly developed screening method for the isolation of cDNAs that increase the degree of gamma-cleavage. Herp was originally identified as a homocysteine-responsive protein, and its expression is up-regulated by endoplasmic reticulum stress. Herp is an endoplasmic reticulum-localized membrane protein that has a ubiquitin-like domain. Here, we report that a high expression of Herp in cells increases the level of Abeta generation, although not in PS-deficient cells. We found that Herp interacts with both PS1 and PS2. Thus, Herp regulates PS-mediated Abeta generation, possibly through its binding to PS. Immunohistochemical analysis of a normal human brain section with an anti-Herp antibody revealed the exclusive staining of neurons and vascular smooth muscle cells. Moreover, the antibody strongly stained activated microglia in senile plaques in the brain of patients with Alzheimer disease. Taken together, Herp could be involved in Abeta accumulation, including the formation of senile plaques and vascular Abeta deposits.
ISSN:0021-9258
DOI:10.1074/jbc.M112372200