The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus
The γ-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus
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DOI：
10.1073/pnas.261463298
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发表时间：
2001-12-18
影响因子：
11.1
通讯作者：
Pimplikar, SW
中科院分区：
文献类型：
--
作者：
Gao, YH;Pimplikar, SW
淀粉样蛋白前体蛋白（APP）通过β-和γ-分泌酶的顺序加工产生A β肽，A β肽是阿尔茨海默病中观察到的老年斑的主要成分。γ-分泌酶的切割也导致59或57个残基长的C-末端片段（C γ）的细胞质释放。这种处理类似于跨膜蛋白如Notch的受调节的膜内蛋白水解，其中释放的细胞质片段进入细胞核并调节基因表达。在这里，我们研究了APP的类似C γ片段是否也在细胞核中发挥作用。我们发现，异位表达的C γ是目前在细胞质和细胞核。有趣的是，C γ 59的表达导致PAT 1（一种与APP胞质结构域相互作用的蛋白质）从细胞核中消失，并诱导其蛋白体降解。用lactacystin处理细胞可防止PAT 1降解并保留其核定位。相比之下，C γ 57（γ-裂解的次要产物）在PAT 1降解中仅略微有效。此外，C γ 59而不是C γ 57有效地抑制视黄酸反应基因的表达。因此，我们的研究提供的证据表明，正如所预测的调节膜内蛋白水解机制，C γ似乎在细胞核中发挥作用。
Sequential processing of the amylold precursor protein (APP) by beta- and gamma -secretases generates the A beta peptide, a major constituent of the senile plaques observed in Alzheimer's disease. The cleavage by gamma -secretase also results in the cytoplasmic release of a 59- or 57-residue-long C-terminal fragment (C gamma). 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 C gamma fragments of APP also exert effects in the nucleus. We find that ectopically expressed C gamma is present both in the cytoplasm and in the nucleus. Interestingly, expression of C gamma 59 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, C gamma 57, a minor product of gamma -cleavage, is only marginally effective in PAT1 degradation. Furthermore, C gamma 59 but not C gamma 57 potently represses retinoic acid-responsive gene expression. Thus, our studies provide the evidence that, as predicted by the regulated intramembrane proteolysis mechanism, C gamma seems to function in the nucleus.