Suppression of APP-containing vesicle trafficking and production of beta-amyloid by AID/DHHC-12 protein.
The metabolism of amyloid beta-protein precursor (APP) is regulated by various cytoplasmic and/or membrane-associated proteins, some of which are involved in the regulation of intracellular membrane trafficking. We found that a protein containing Asp-His-His-Cys (DHHC) domain, alcadein and APP interacting DHHC protein (AID)/DHHC-12, strongly inhibited APP metabolism, including amyloid beta-protein (Abeta) generation. In cells expressing AID/DHHC-12, APP was tethered in the Golgi, and APP-containing vesicles disappeared from the cytoplasm. Although DHHC domain-containing proteins are involved in protein palmitoylation, a AID/DHHC-12 mutant of which the enzyme activity was impaired by replacing the DHHC sequence with Ala-Ala-His-Ser (AAHS) made no detectable difference in the generation and trafficking of APP-containing vesicles in the cytoplasm or the metabolism of APP. Furthermore, the mutant AID/DHHC-12 significantly increased non-amyloidogenic alpha-cleavage of APP along with activation of a disintegrin and metalloproteinase 17, a major alpha-secretase, suggesting that protein palmitoylation involved in the regulation of alpha-secretase activity. AID/DHHC-12 can modify APP metabolism, including Abeta generation in multiple ways by regulating the generation and/or trafficking of APP-containing vesicles from the Golgi and their entry into the late secretary pathway in an enzymatic activity-independent manner, and the alpha-cleavage of APP in the enzymatic activity-dependent manner.
Mizumaru
Chie
C
Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Saito
Yuhki
Y
Ishikawa
Takao
T
Yoshida
Tomohiro
T
Yamamoto
Tohru
T
Nakaya
Tadashi
T
Suzuki
Toshiharu
T
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D051839:NFI Transcription Factors / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport / Q000502:physiology; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051839:NFI Transcription Factors; D010446:Peptide Fragments; D014404:Tubulin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase