14-3-3 targets chaperone-associated misfolded proteins to aggresomes

Abstract

The aggresome is a key cytoplasmic organelle for sequestration and clearance of toxic protein aggregates. While loading misfolded proteins cargos to dynein motors has been recognized as an important step in the aggresome formation process, the molecular machinery mediating the association of cargos with the dynein motor is poorly understood. Here, we report a new aggresomal targeting pathway involving 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 aggresome formation 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.