BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

Bcl2-associated athanogene (BAG) proteins are a family of co-chaperones that interact with the ATPase domain of the heat shock protein (Hsp) 70 through a specific structural domain known as BAG domain (110-124 amino acids). 1, 2 Members of the family are found throughout the evolution in yeast (Saccharomyces cerevisiae, Schizosaccharomyces pombe), invertebrates (Caenorhabditis elegans, Ciona intestinalis, Drosophila), amphibians (Xenopus laevis), mammals (humans, mice) and plants (Oryza sativa, Arabidopsis thaliana), 1,3-6 suggesting a fundamental biological role. BAG3 was originally identified by yeast two-hybrid screening using the ATPase domain of the Hsp (heat shock cognate (Hsc)/Hsp) 70 as a bait. 1 In addition to the BAG domain, BAG3 contains a WW domain and a proline-rich repeat (PXXP; Figure 1a ) that mediate binding to other partners. 1, 7, 8 Here we will outline the roles so far identified of BAG3 in the regulation of major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy. By modulating these pathways, BAG3 appears to mediate cell adaptive responses to stressful stimuli, and its alterations result in altered homeostasis and reduced cytoprotection, explaining why its expression is often found deregulated in a vast series of tumors.