The BAG3-dependent and -independent roles of cardiac small heat shock proteins

Abstract

Small heat shock proteins (sHSPs) comprise an important protein family that is ubiquitously expressed, is highly conserved among species, and has emerged as a critical regulator of protein folding. While these proteins are functionally important for a variety of tissues, an emerging field of cardiovascular research reveals sHSPs are also extremely important for maintaining normal cardiac function and regulating the cardiac stress response. Notably, numerous mutations in genes encoding sHSPs have been associated with multiple cardiac diseases. sHSPs (HSPB5, HSPB6, and HSPB8) have been described as mediating chaperone functions within the heart by interacting with the cochaperone protein BCL-2-associated anthanogene 3 (BAG3); however, recent reports indicate that sHSPs (HSPB7) can perform other BAG3-independent functions. Here, we summarize the cardiac functions of sHSPs and present the notion that cardiac sHSPs function via BAG3-dependent or -independent pathways.

Figure 1. Comparison of cardiac sHSP sequences.

Reference sequences of human sHSPs were retrieved from Uniprot database and aligned using Kalign (129). Secondary structure of the α-crystallin domain (green box) was annotated based on NMR structure of αB-crystallin (PDB ID: 2KLR) (130).

Figure 2. Reduction of cardiac sHSP levels in BAG3-cKO mice correlates with their affinity for BAG3.

The x axis (red lines) shows the dissociation constant (K_D) between sHSP and BAG3. A lower K_D value indicates a stronger interaction between the respective sHSP and BAG3. K_D values between sHSP and BAG3 were obtained from Raush et al. (23), and Vos et al. (27) reported the absence of affinity (infinite K_D) between HSPB7 and BAG3. The y axis (blue lines) shows cardiac levels of sHSP protein in BAG3-cKO mice relative to WT mice. Cardiac levels of sHSPs in BAG3-cKO mice were obtained from Fang et al. (28). Infinite K_D indicates no binding.

Figure 3. The BAG3-dependent and -independent pathways of cardiac sHSPs.

HSPB5/6/8 represent the BAG3-dependent sHSPs (left), in which HSPB5/6/8 physically and functionally interact with BAG3 to form a multichaperone complex that prevents unfolded substrates from becoming insoluble in cardiomyocytes. HSPB7 represents the BAG3-independent cardiac sHSP (right) that binds to monomeric actin and limits its availability for polymerization. However, it is still unknown whether HSPB7 carries out chaperone activity in vivo. SBD, substrate-binding domain; NBD, nucleotide-binding domain. Illustrated by Rachel Davidowitz.