BAG3: a multifaceted protein that regulates major cell pathways

Abstract

Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110-124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression.

Figure 1

(a) Human BAG family proteins. All six reported BAG proteins contain a BAG domain at their C-terminus. Some BAG proteins contain other domains including nuclear localization signal (NLS), ubiquitin-like (UBL) domain, WW domain and proline-rich regions (PXXP). Numbers next to the linear peptide sequence indicate amino acid number in the proteins. (b) Schematic representation of the full-length BAG3 protein and the shorter BAG3 protein found to be associated to synaptosomes

Figure 2

Mechanism of BAG3 activity on (a) client proteins, (b) client mRNAs