HtrA2 regulates β-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation
HtrA2 regulates β-amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation
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DOI：
10.1074/jbc.m702951200
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发表时间：
2007-09-21
影响因子：
4.8
通讯作者：
Kovacs, Dora M.
中科院分区：
文献类型：
--
作者：
Huttunen, Henri J.;Guenette, Suzanne Y.;Kovacs, Dora M.
阿尔茨海默病相关的β-淀粉样多肽是由其前体蛋白APP产生的。通过酵母双杂交实验，我们鉴定了HtrA2/Omi，一种应激反应的伴侣蛋白，是一种与APP N末端富含半胱氨酸的区域结合的蛋白质。HtrA2与细胞裂解产物中未成熟的APP以及小鼠脑提取液进行免疫共沉淀，并在体外降解APP。HtrA2的一个亚群位于内质网(ER)膜的胞液侧，在那里它与蛋白酶体一起参与ER相关的APP的降解，抑制蛋白酶体导致APP的逆转位形式积累，并增加APP与HtrA2和Derlin-1在微粒体膜中的结合。在缺乏HtrA2的细胞中，APP全蛋白稳定并在早期分泌途径中积累，与APP C末端片段水平升高和ALL分泌增加相关。抑制ER相关的降解(HtrA2或蛋白酶体)促进APP与COPII蛋白Sec23的结合，表明APP增加了APP向外的运输。基于这些结果，我们提出了HtrA2的一个新功能，即通过ER相关的降解来调节APP的代谢。
Alzheimer disease-associated beta-amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a protein binding to the N-terminal cysteine-rich region of APP. HtrA2 coimmunoprecipitates exclusively with immature APP from cell lysates as well as mouse brain extracts and degrades APP in vitro. A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic reticulum (ER) membrane where it contributes to ER-associated degradation of APP together with the proteasome, Inhibition of the proteasome results in accumulation of retrotranslocated forms of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes. In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in the early secretory pathway correlating with elevated levels of APP C-terminal fragments and increased All secretion. Inhibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPII protein Sec23 suggesting enhanced trafficking of APP out of the ER. Based on these results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associated degradation.