title: 14-3-3 protein targets misfolded chaperone-associated proteins to aggresomes.
abstract: The aggresome is a key cytoplasmic organelle for sequestration and clearance of toxic protein aggregates. Although loading misfolded proteins cargos to dynein motors has been recognized as an important step in the aggresome formation process, the molecular machinery that mediates the association of cargos with the dynein motor is poorly understood. Here, we report a new aggresome-targeting pathway that involves isoforms of 14-3-3, a family of conserved regulatory proteins. 14-3-3 interacts with both the dynein-intermediate chain (DIC) and an Hsp70 co-chaperone Bcl-2-associated athanogene 3 (BAG3), thereby recruiting chaperone-associated protein cargos to dynein motors for their transport to aggresomes. This molecular cascade entails functional dimerization of 14-3-3, which we show to be crucial for the formation of aggresomes in both yeast and mammalian cells. These results suggest that 14-3-3 functions as a molecular adaptor to promote aggresomal targeting of misfolded protein aggregates and may link such complexes to inclusion bodies observed in various neurodegenerative diseases.
authors.affiliation: Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.forename: Kourtney
authors.initials: K
authors.lastname: Graham
authors.forename: Molly
authors.initials: M
authors.lastname: Foote
authors.forename: Fengshan
authors.initials: F
authors.lastname: Liang
authors.forename: Raed
authors.initials: R
authors.lastname: Rizkallah
authors.forename: Myra
authors.initials: M
authors.lastname: Hurt
authors.forename: Yanchang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D004398:Dyneins; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D048948:14-3-3 Proteins; D018832:Molecular Chaperones; D011506:Proteins; D004398:Dyneins
keywords: 14-3-3; Adaptor; Aggresome; BAG3; Dynein