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Ubiquitin regulates GGA3-mediated degradation of BACE1.

Abstract
BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1) is a membrane-tethered member of the aspartyl proteases, essential for the production of beta-amyloid, a toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. The BACE1 C-terminal fragment contains a DXXLL motif that has been shown to bind the VHS (VPS27, Hrs, and STAM) domain of GGA1-3 (Golgi-localized gamma-ear-containing ARF-binding proteins). GGAs are trafficking molecules involved in the transport of proteins containing the DXXLL signal from the Golgi complex to endosomes. Moreover, GGAs bind ubiquitin and traffic synthetic and endosomal ubiquitinated cargoes to lysosomes. We have previously shown that depletion of GGA3 results in increased BACE1 levels and activity because of impaired lysosomal degradation. Here, we report that the accumulation of BACE1 is rescued by the ectopic expression of GGA3 in H4 neuroglioma cells depleted of GGA3. Accordingly, the overexpression of GGA3 reduces the levels of BACE1 and beta-amyloid. We then established that mutations in the GGA3 VPS27, Hrs, and STAM domain (N91A) or in BACE1 di-leucine motif (L499A/L500A), able to abrogate their binding, did not affect the ability of ectopically expressed GGA3 to rescue BACE1 accumulation in cells depleted of GGA3. Instead, we found that BACE1 is ubiquitinated at lysine 501 and is mainly monoubiquitinated and Lys-63-linked polyubiquitinated. Finally, a GGA3 mutant with reduced ability to bind ubiquitin (GGA3L276A) was unable to regulate BACE1 levels both in rescue and overexpression experiments. These findings indicate that levels of GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery.
AuthorsEugene L Kang, Andrew N Cameron, Fabrizio Piazza, Kendall R Walker, Giuseppina Tesco
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 31 Pg. 24108-19 (Jul 30 2010) ISSN: 1083-351X [Electronic] United States
PMID20484053 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Adaptor Proteins, Vesicular Transport
  • Amyloid beta-Peptides
  • GGA adaptor proteins
  • Ubiquitin
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • Bace1 protein, mouse
Topics
  • Adaptor Proteins, Vesicular Transport (chemistry)
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases (chemistry)
  • Amyloid beta-Peptides (chemistry)
  • Animals
  • Aspartic Acid Endopeptidases (chemistry)
  • Endosomes (metabolism)
  • Gene Expression Regulation
  • Golgi Apparatus (metabolism)
  • Humans
  • Lysosomes (chemistry, metabolism)
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Ubiquitin (chemistry)

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