PDZ domain-dependent suppression of NF-kappaB/p65-induced Abeta42 production by a neuron-specific X11-like protein

J Biol Chem. 2000 Apr 28;275(17):13056-60. doi: 10.1074/jbc.c000019200.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Brain / metabolism
  • COS Cells
  • Cell Line
  • DNA, Complementary / metabolism
  • Gene Expression Regulation
  • Gene Library
  • Humans
  • Luciferases / metabolism
  • NF-kappa B / chemistry
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • NF-kappa B p50 Subunit
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Precipitin Tests
  • Protein Binding
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Transcription Factor RelA
  • Transcription, Genetic
  • Transfection
  • Two-Hybrid System Techniques

Substances

  • APBA1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • DNA, Complementary
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Protein Isoforms
  • Transcription Factor RelA
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Luciferases