Inhibition of APP intracellular domain (AICD) transcriptional activity via covalent conjugation with Nedd8.
The processing of amyloid precursor protein (APP) by gamma-secretase generates the APP intracellular domain (AICD), which functions as a transcriptional factor for target gene activation following localization into the nucleus. In this study, we demonstrate that AICD could be modified via covalent conjugation with Nedd8, a ubiquitin-like protein. Domain analysis and site-directed substitution of neddylation sites showed that multiple lysine residues of the APP C-terminal C99 fragment including AICD were acceptor sequences for Nedd8 conjugation. AICD-mediated transcriptional activation was inhibited by Nedd8 conjugation. Furthermore, the transcriptional activity of the neddylation-defective AICD mutant was not altered by Nedd8 expression. Nedd8 conjugation of AICD inhibited its interaction with Fe65, and consequently resulted in the impairment of AICD-Fe65-Tip60 complex formation for the transcriptional activation of the target gene. These results illustrate the regulatory mechanisms by which AICD transcriptional activity might be regulated via covalent conjugation with Nedd8.
Lee
Mi-Ra
MR
Department of Biological Science, Sungkyunkwan University, 300 Chunchundong, Suwon 440-746, Republic of Korea.
Lee
Deresa
D
Shin
Soo Kyung
SK
Kim
Young Ho
YH
Choi
Cheol Yong
CY
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics*; D002460:Cell Line; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008969:Molecular Sequence Data; D000075687:NEDD8 Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015533:Transcriptional Activation; D014452:Ubiquitins / Q000378:metabolism*
C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014452:Ubiquitins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5