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Review
. 2017 Jun 21:10:177.
doi: 10.3389/fnmol.2017.00177. eCollection 2017.

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

Elisabeth Stürner  1 , Christian Behl  1
Affiliations
Review

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

Elisabeth Stürner et al. Front Mol Neurosci. .

Abstract

In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3). Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer's disease (tau-protein), Huntington's disease (mutated huntingtin/polyQ proteins), and amyotrophic lateral sclerosis (mutated SOD1). In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate.

Keywords: BAG3; neurodegenerative disorders; protein quality control; proteostasis; selective macroautophagy.

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Figures

FIGURE 1
FIGURE 1
The cellular proteostasis network and its degradation systems. In cellular protein quality control, molecular chaperone systems function in concert with protein transport and degradation systems to ensure cellular proteostasis. In addition to the ubiquitin-proteasome system, the autophagy-lysosome system mediates the disposal of degradation-prone substrates.
FIGURE 2
FIGURE 2
Scheme of selective macroautophagy. Macroautophagy represents a complex multi-step process. After the initiation of macroautophagy (1: Initiation) a phagophore is formed at the phagophore assembly site (PAS) (2: Nucleation). Subsequently, the phagophore expands by recruiting membranes derived from different intracellular sources (3: Elongation) and thereby sequesters the cargo. The closing of the phagophore results in the formation of a mature autophagosome. Following its transport to the lysosome, the autophagosome fuses with the lysosome (4: Fusion), generating an autolysosome. Within the autolysosome, the enclosed material is degraded (5: Degradation).
FIGURE 3
FIGURE 3
Modular protein structure of BAG3. BAG3 is encoded by four exons (Coding sequence). The BAG3 protein comprises various characteristic amino acid motifs/regions and domains which permit the interaction of BAG3 with numerous proteins involved in many cellular key pathways. In addition to its conserved BAG domain, BAG3 contains a conserved WW domain, two IPV motifs, two 14-3-3 binding motifs and a PxxP region. Moreover, a caspase cleavage site was identified in the PxxP region (344KEVD) of BAG3 and at its very C-terminus (515LEAD). The BAG3 protein is suggested to be phosphorylated at the indicated serine and tyrosine residues.
FIGURE 4
FIGURE 4
BAG1-BAG3 switch in expression and function. The BAG1 and BAG3 expression levels are reciprocally regulated during cellular aging and under acute stress. Under physiological conditions, a high BAG1 expression, but a low BAG3 expression could be detected; while under pathophysiological conditions, the BAG3 level is elevated and the BAG1 level is decreased. The BAG1 to BAG3 expression switch is accompanied by a functional switch from HSP70-BAG1-mediated proteasomal degradation to HSP70-BAG3-mediated selective macroautophagy.
FIGURE 5
FIGURE 5
Model of BAG3-mediated aggresome-targeting and selective macroautophagy. During aging and under acute cellular stress, misfolded proteins and/or aggregates bind to a multi-chaperone complex consisting of HSPB8, HSP70, HSP40, BAG3, 14-3-3γ, and STUB1. Subsequently, BAG3 mediates in concert with the 14-3-3γ protein the association of this complex with the dynein complex and thereby initiates the microtubule-based retrograde transport of the degradation-prone substrates to the aggresome. BAG3 induces the selective macroautophagy of the substrates by complexing with the macroautophagy receptor protein p62 that interacts simultaneously with both the substrate as well as the autophagosome membrane-associated protein LC3. The substrates are finally degraded by the autophagic-lysosomal system.
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