The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus

doi:10.1073/pnas.261463298

The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus

Yuehua Gao and
Sanjay W. Pimplikar*

Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106

Edited by Kai Simons, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, and approved October 16, 2001 (received for review August 31, 2001)

Abstract

Sequential processing of the amyloid precursor protein (APP) by β- and γ-secretases generates the Aβ peptide, a major constituent of the senile plaques observed in Alzheimer's disease. The cleavage by γ-secretase also results in the cytoplasmic release of a 59- or 57-residue-long C-terminal fragment (Cγ). This processing resembles regulated intramembrane proteolysis of transmembrane proteins such as Notch, where the released cytoplasmic fragments enter the nucleus and modulate gene expression. Here, we examined whether the analogous Cγ fragments of APP also exert effects in the nucleus. We find that ectopically expressed Cγ is present both in the cytoplasm and in the nucleus. Interestingly, expression of Cγ59 causes disappearance of PAT1, a protein that interacts with the APP cytoplasmic domain, from the nucleus and induces its proteosomal degradation. Treatment of cells with lactacystin prevents PAT1 degradation and retains its nuclear localization. By contrast, Cγ57, a minor product of γ-cleavage, is only marginally effective in PAT1 degradation. Furthermore, Cγ59 but not Cγ57 potently represses retinoic acid-responsive gene expression. Thus, our studies provide the evidence that, as predicted by the regulated intramembrane proteolysis mechanism, Cγ seems to function in the nucleus.

Footnotes

↵ * To whom reprint requests should be addressed at: Institute of Pathology, Case Western Reserve University, BRB-920, 10900 Euclid Avenue, Cleveland, OH 44106-4943. E-mail: swp{at}po.cwru.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

APP,

amyloid precursor protein;

Cγ,

C-terminal fragment cleaved by γ-secretase;

RIP,

regulated intramembrane proteolysis;

NICD,

Notch intracellular domain;

GFP,

green fluorescent protein;

ER-α,

estrogen receptor-α;

RA,

retinoic acid;

RAR,

RA receptor;

CTF,

cytoplasmic fragment