Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration

J Biol Chem. 2016 Aug 12;291(33):17209-27. doi: 10.1074/jbc.M116.733626. Epub 2016 Jun 20.


The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1). Noteworthy, APLP2, but not APLP1, interacts with Stub1 and CRL4(CRBN), pointing to a functional pathway shared only by APP and APLP2. In vitro ubiquitination/ubiquitome analysis indicates that these E3 ligases are enzymatically active and ubiquitinate the ACR residues Lys(649/650/651/676/688) Deletion of Crbn reduces ubiquitination of Lys(676) suggesting that Lys(676) is physiologically ubiquitinated by CRL4(CRBN) The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible.

Keywords: Alzheimer disease; CRL4CRBN; Cereblon; E3 ubiquitin ligase; Intellectual disability; amyloid precursor protein (APP); neurodegenerative disease; ubiquitylation (ubiquitination).

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mice
  • Multienzyme Complexes / genetics
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Synaptic Transmission*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination*
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Protein Precursor
  • Aplp1 protein, mouse
  • Aplp2 protein, mouse
  • Apolipoproteins E
  • Crbn protein, mouse
  • Cul4B protein, mouse
  • Cul4a protein, mouse
  • Cullin Proteins
  • DNA-Binding Proteins
  • Ddb1 protein, mouse
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • tau Proteins
  • Stub1 protein, mouse
  • Ubiquitin-Protein Ligases