14-3-3 and aggresome formation: implications in neurodegenerative diseases

Abstract

Protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative diseases. In addition to chaperone-mediated refolding and proteasomal degradation, the aggresome-macroautophagy pathway has emerged as another defense mechanism for sequestration and clearance of toxic protein aggregates in cells. Previously, the 14-3-3 proteins were shown to be indispensable for the formation of aggresomes induced by mutant huntingtin proteins. In a recent study, we have determined that 14-3-3 functions as a molecular adaptor to recruit chaperone-associated misfolded proteins to dynein motors for transport to aggresomes. This molecular complex involves a dimeric binding of 14-3-3 to both the dynein-intermediate chain (DIC) and an Hsp70 co-chaperone Bcl-2-associated athanogene 3 (BAG3). As 14-3-3 has been implicated in various neurodegenerative diseases, our findings may provide mechanistic insights into its role in managing misfolded protein stress during the process of neurodegeneration.

Keywords: 14-3-3; aggresomes; chaperones; inclusion bodies; neurodegeneration; protein aggregation; protein misfolding.

Figure 1. Model for 14-3-3’s role in the aggresome-macroautophagy pathway. Numbers denote various steps during aggresome formation and clearance. A 14-3-3 dimer simultaneously binds to phosphorylated BAG3 and the dynein motor, thereby targeting chaperone-associated misfolded proteins and aggregates to the aggresome.