磷酸化早老素 1 通过促进自噬体-溶酶体融合来减少β-淀粉样蛋白。
Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome-lysosome fusion.
机构信息
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065.
出版信息
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7148-7153. doi: 10.1073/pnas.1705240114. Epub 2017 May 22.
Presenilin 1 (PS1), the catalytic subunit of the γ-secretase complex, cleaves βCTF to produce Aβ. We have shown that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 decreases Aβ levels by increasing βCTF degradation through autophagy. Here, we report the molecular mechanism by which PS1 modulates βCTF degradation. We show that PS1 phosphorylated at Ser367, but not nonphosphorylated PS1, interacts with Annexin A2, which, in turn, interacts with the lysosomal -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Vamp8. Annexin A2 facilitates the binding of Vamp8 to the autophagosomal SNARE Syntaxin 17 to modulate the fusion of autophagosomes with lysosomes. Thus, PS1 phosphorylated at Ser367 has an antiamyloidogenic function, promoting autophagosome-lysosome fusion and increasing βCTF degradation. Drugs designed to increase the level of PS1 phosphorylated at Ser367 should be useful in the treatment of Alzheimer's disease.
早老素 1（PS1）是 γ-分泌酶复合物的催化亚基，它切割βCTF 产生 Aβ。我们已经表明，PS1 通过一种独特的双功能机制调节 Aβ 水平。除了其作为 γ-分泌酶复合物的催化亚基的已知作用外，PS1 在 Ser367 上的选择性磷酸化通过增加自噬介导的βCTF 降解来降低 Aβ 水平。在这里，我们报告了 PS1 调节 βCTF 降解的分子机制。我们表明，PS1 在 Ser367 上磷酸化，但不是非磷酸化的 PS1，与膜联蛋白 A2 相互作用，而膜联蛋白 A2 又与溶酶体-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）Vamp8 相互作用。膜联蛋白 A2 促进 Vamp8 与自噬体 SNARE Syntaxin 17 的结合，从而调节自噬体与溶酶体的融合。因此，PS1 在 Ser367 上磷酸化具有抗淀粉样蛋白形成功能，促进自噬体-溶酶体融合并增加 βCTF 降解。旨在增加 PS1 在 Ser367 上磷酸化水平的药物应该对阿尔茨海默病的治疗有用。
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