Extracellular release of BACE1 holoproteins from human neuronal cells.
BACE1 is a membrane-bound aspartyl protease involved in production of the Alzheimer's amyloid beta-protein. The BACE1 ectodomain is partially cleaved to generate soluble BACE1, but the physiological significance of this event is unclear. During our characterization of BACE1 shedding from human neuroblastoma SH-SY5Y cells stably expressing BACE1, we unexpectedly found that detectable amounts of BACE1 holoproteins were released extracellularly along with soluble BACE1. Treatment with the metalloprotease inhibitor, TAPI-1, inhibited BACE1 shedding but increased BACE1 holoprotein release. Soluble and full-length BACE1 were released in parallel, at least partly originating from the plasma membrane. Furthermore, the release of soluble BACE1, but not full-length BACE1, was increased by deletion of the C-terminal dileucine motif, indicating that dysregulated BACE1 sorting affects BACE1 shedding. These findings suggest that the release of BACE1 holoproteins may be a physiologically relevant cellular process.
Murayama
Kiyoko S
KS
Department of Demyelinating Disease and Aging, National Institute of Neuroscience, NCNP, Kodaira, Tokyo 187-8502, Japan.
Kametani
Fuyuki
F
Araki
Wataru
W
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001665:Binding Sites; D002460:Cell Line; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D013329:Structure-Activity Relationship
D020033:Protein Isoforms; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human