The Multifunctional Protein BAG3: A Novel Therapeutic Target in Cardiovascular Disease

Abstract

The B-cell lymphoma 2-associated anthanogene (BAG3) protein is expressed most prominently in the heart, the skeletal muscle, and in many forms of cancer. In the heart, it serves as a co-chaperone with heat shock proteins in facilitating autophagy; binds to B-cell lymphoma 2, resulting in inhibition of apoptosis; attaches actin to the Z disk, providing structural support for the sarcomere; and links the α-adrenergic receptor with the L-type Ca²⁺ channel. When BAG3 is overexpressed in cancer cells, it facilitates prosurvival pathways that lead to insensitivity to chemotherapy, metastasis, cell migration, and invasiveness. In contrast, in the heart, mutations in BAG3 have been associated with a variety of phenotypes, including both hypertrophic/restrictive and dilated cardiomyopathy. In murine skeletal muscle and vasculature, a mutation in BAG3 leads to critical limb ischemia after femoral artery ligation. An understanding of the biology of BAG3 is relevant because it may provide a therapeutic target in patients with both cardiac and skeletal muscle disease.

Keywords: BAG3; apoptosis; autophagy; heart failure.

Graphical abstract

Figure 1

The Structure of BAG3 and its Protein-Binding Domains The consensus protein-binding domains in B-cell lymphoma 2 (Bcl-2)–associated anthanogene (BAG3) (WW, IPV, PXXP, and BAG) and the putative signaling pathways that are regulated in cancer cells through each binding domain are shown. Numbers are amino acids. αB-crystallin = small heat shock protein B5 (HSPB5); CASA = chaperone-assisted selective autophagy; Hsc70/Hsp70 = constitutively expressed and the inducible heat shock protein 70; Hsp = heat shock protein; PLC-γ = phospholipase C-gamma; SH3 = SRC homology 3 domain.

Central Illustration

The Pleiotropic Effects of BAG3 The major pathways are illustrated through which BAG3 acts to mediate its primary functions in the heart: facilitation of autophagy, inhibition of apoptosis, maintenance of adrenergic responsiveness and excitation–contraction coupling, support of the sarcomere, and modulation of gene expression. αG_s = alpha subunit of the guanine nucleotide binding protein; β₁-AR = β₁-adrenergic receptor; AC = adenylyl cyclase; ATP = adenosine triphosphate; BAD = B-cell lymphoma-2–associated death; Bax = B-cell lymphoma-2–associated X protein; BAK = B-cell lymphoma-2 homologous promoter; antagonist/killer; Bcl-2 = B-cell lymphoma-2; cAMP = cyclic adenosine monophosphate; Ca_v-1.2 = L-type Ca²⁺ channel; Cyt C = cytochrome C; FOX M1 = Forkhead box 14 M1 transcription factor; HIF 1α = hypoxia-inducible factor 1 active transcription factor; LATS = serine/threonine protein kinase; LC3 = microtubule-associated protein 1A/B-light chain 3; p53 = tumor suppressor protein; SR = sarcoplasmic reticulum; PKA = protein kinase A; SYNPO2 = protein coding gene synaptopodin 2; Tomm20 = mitochondrial import receptor subunit TOM20 homolog; VDAC = voltage-dependent anion channel; YAP = yes-associated transcriptional regulator; YAZ = transcription factor; other abbreviations as in Figure 1.

Figure 2

Molecular Pathology of BAG3-Mediated Autophagy During Hypoxia-Reoxygenation The figure illustrates the multiple pathways through which B-cell lymphoma 2 (Bcl-2)–associated anthanogene (BAG3) acts to mediate autophagy and how the expression of green fluorescent protein (GFP) (green)–red fluorescent protein (RFP) (red-orange) reporter gene can be used to quantify autophagy flux.