One BAG doesn't fit all: the differences and similarities of BAG family members in mediating CNS homeostasis

Abstract

There is an increasing awareness that B-cell lymphoma 2 (Bcl-2)-associated athanogene (BAG) proteins play critical roles in maintaining neural homeostasis, and that their dysregulation contributes to neurological disorders. This protein family of nine members is evolutionarily conserved, with each member having at least one BAG domain that binds to the nucleotide-binding domains of Heat Shock Protein (Hsp) 70 family members. Collectively, these proteins are essential for the proper functioning of the central nervous system (CNS). Although there are numerous studies that focus on a specific BAG protein, an understanding of how BAG family members may act cooperatively to maintain cellular homeostasis is needed. In this review, we give an overview of the BAG domain interactors, Hsp72, Hsp70.2, CHIP and METTL3 which are common to all BAG family members. This is followed by a concise description of each BAG family member, with a focus on its function in the CNS and dysfunction in neurological conditions. Finally, we discuss the intersection of the molecular functions of the different BAG family proteins by delineating differences and similarities, and describing how their functions can be either complementary or competing. The information in this review provides a basic conceptual framework for analyzing the roles of a particular BAG family member in the CNS and neurological conditions. This review also provides a basis for examining how BAG family members can play either redundant or antagonistic roles that may modulate experimental outcomes.