Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
J Biol Chem. 2010 Oct 15;285(42):32549-56. doi: 10.1074/jbc.M110.128439. Epub 2010 Jul 30.
Processing of the amyloid precursor protein (APP) by β- and γ-secretases generates pathogenic β-amyloid (Aβ) peptides associated with Alzheimer disease (AD), whereas cleavage of APP by α-secretases precludes Aβ formation. Little is known about the role of α-secretase cleavage in γ-secretase regulation. Here, we show that α-secretase-cleaved APP C-terminal product (αCTF) functions as an inhibitor of γ-secretase. We demonstrate that the substrate inhibitory domain (ASID) within αCTF, which is bisected by the α-secretase cleavage site, contributes to this negative regulation because deleting or masking this domain turns αCTF into a better substrate for γ-secretase. Moreover, α-secretase cleavage can potentiate the inhibitory effect of ASID. Inhibition of γ-secretase activity by αCTF is observed in both in vitro and cellular systems. This work reveals an unforeseen role for α-secretase in generating an endogenous γ-secretase inhibitor that down-regulates the production of Aβ. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD.
淀粉样前体蛋白（APP）经β-和γ-分泌酶切割产生与阿尔茨海默病（AD）相关的致病β-淀粉样肽（Aβ），而 APP 经α-分泌酶切割则阻止了 Aβ的形成。α-分泌酶切割在 γ-分泌酶调节中的作用知之甚少。在这里，我们表明α-分泌酶切割的 APP C 端产物（αCTF）作为 γ-分泌酶的抑制剂发挥作用。我们证明了 αCTF 内的底物抑制结构域（ASID），该结构域被 α-分泌酶切割位点分隔，有助于这种负调控，因为删除或掩盖该结构域会使 αCTF 成为 γ-分泌酶的更好底物。此外，α-分泌酶切割可以增强 ASID 的抑制作用。αCTF 在体外和细胞系统中均观察到对 γ-分泌酶活性的抑制。这项工作揭示了α-分泌酶在产生内源性γ-分泌酶抑制剂方面的意外作用，该抑制剂下调了 Aβ的产生。这种反馈机制的失调可能导致 AD 的发病机制。
