PDZ domain-dependent suppression of NF-kappaB/p65-induced Abeta42 production by a neuron-specific X11-like protein.
It is widely believed that one of the causes of Alzheimer's disease (AD) is the generation and secretion of beta-amyloid (Abeta) from amyloid precursor protein in the brain. Here we report that a transcription factor, NF-kappaB/p65, induces increased secretion of amyloidogenic Abeta42 but not Abeta40. The kappaB motif-dependent production of Abeta42 was suppressed by binding of NF-kappaB/p65 to the PDZ domain of the X11-like protein (X11L), which a human homologue protein of LIN-10. The results suggest that the PDZ domain of X11L can control the ability of NF-kappaB/p65 to induce expression of protein(s) involved in Abeta42 production. The amino acids 161-163 in Rel homology domain (RHD) of NF-kappaB/p65 is important in interaction of NF-kappaB/p65 with X11L. Another subunit NF-kappaB/p50 and heterodimers of p65 and p50 do not bind to X11L. Our finding indicates NF-kappaB and X11L may, in novel way, regulate Abeta production in neuronal cells. Targeting X11L by specific therapy may provide the possibility to control the progression of AD.
Tomita
S
S
Laboratory of Neurobiophysics, School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Fujita
T
T
Kirino
Y
Y
Suzuki
T
T
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D005786:Gene Expression Regulation; D015723:Gene Library; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D014162:Transfection; D020798:Two-Hybrid System Techniques
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D018076:DNA, Complementary; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D051996:Transcription Factor RelA; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D008156:Luciferases