Cao Xinwei, Südhof Thomas C
Center for Basic Neuroscience, Department of Molecular Genetics, and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
J Biol Chem. 2004 Jun 4;279(23):24601-11. doi: 10.1074/jbc.M402248200. Epub 2004 Mar 24.
Amyloid-beta precursor protein (APP) forms a transcriptionally active complex with the adaptor protein Fe65 and the histone acetyltransferase Tip60, but the mechanism of transcriptional activation that is mediated by APP and Fe65 remains unclear. APP is cleaved by gamma-secretase similar to Notch, whose intracellular domain activates transcription by interacting with nuclear transcription factors. To test whether the APP intracellular domain (AICD) functions analogously, we investigated how APP and Fe65 transactivate a Gal4 fusion protein of Tip60. Consistent with the Notch paradigm, we observe that gamma-cleavage of APP and nuclear translocation of Fe65 are required for transactivation. Surprisingly, however, we find that nuclear translocation of the AICD may be dispensable and that only membrane-tethered AICD (i.e. AICD coupled to a transmembrane region) and not free AICD (i.e. soluble AICD) is a potent transactivator of transcription. Membrane-tethered AICD recruits Fe65 and mediates the activation of bound Fe65 that is then released for nuclear translocation by gamma-cleavage together with the AICD. Our data suggest that transcriptional transactivation by APP and Notch may involve distinct mechanisms; whereas the Notch intracellular domain directly functions in the nucleus, the AICD acts indirectly by activating Fe65.
淀粉样前体蛋白（APP）与衔接蛋白Fe65和组蛋白乙酰转移酶Tip60形成转录活性复合物，但APP和Fe65介导的转录激活机制仍不清楚。APP与Notch类似，可被γ-分泌酶切割，其胞内结构域通过与核转录因子相互作用来激活转录。为了测试APP胞内结构域（AICD）是否具有类似功能，我们研究了APP和Fe65如何反式激活Tip60的Gal4融合蛋白。与Notch模式一致，我们观察到APP的γ-切割和Fe65的核转位是反式激活所必需的。然而，令人惊讶的是，我们发现AICD的核转位可能是不必要的，只有膜结合的AICD（即与跨膜区域偶联的AICD）而非游离的AICD（即可溶性AICD）是转录的有效反式激活剂。膜结合的AICD招募Fe65并介导结合的Fe6
