The role of heat shock proteins and co-chaperones in heart failure

Abstract

The ongoing contractile and metabolic demands of the heart require a tight control over protein quality control, including the maintenance of protein folding, turnover and synthesis. In heart disease, increases in mechanical and oxidative stresses, post-translational modifications (e.g., phosphorylation), for example, decrease protein stability to favour misfolding in myocardial infarction, heart failure or ageing. These misfolded proteins are toxic to cardiomyocytes, directly contributing to the common accumulation found in human heart failure. One of the critical class of proteins involved in protecting the heart against these threats are molecular chaperones, including the heat shock protein70 (HSP70), HSP90 and co-chaperones CHIP (carboxy terminus of Hsp70-interacting protein, encoded by the Stub1 gene) and BAG-3 (BCL2-associated athanogene 3). Here, we review their emerging roles in the maintenance of cardiomyocytes in human and experimental models of heart failure, including their roles in facilitating the removal of misfolded and degraded proteins, inhibiting apoptosis and maintaining the structural integrity of the sarcomere and regulation of nuclear receptors. Furthermore, we discuss emerging evidence of increased expression of extracellular HSP70, HSP90 and BAG-3 in heart failure, with complementary independent roles from intracellular functions with important therapeutic and diagnostic considerations. While our understanding of these major HSPs in heart failure is incomplete, there is a clear potential role for therapeutic modulation of HSPs in heart failure with important contextual considerations to counteract the imbalance of protein damage and endogenous protein quality control systems.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Keywords: BAG-3; HSP70; HSP90; Stub1; carboxy terminus of HSP70-interacting protein; heart failure.

Figure 1.

A schematic of the way molecular chaperones maintain cardiomyocyte protein quality control. (a) Molecular chaperones (i.e. HSP70, HSP90, CHIP and BAG-3) are critical in maintaining a protein's native folding and function in the face of cardiac stress, mutations and improper folding induced by post-translational modifications (e.g., phosphorylation). (b) When misfolded proteins interact with chaperones (which cannot be refolded), they can be shuttled (c) for ubiquitin-dependent proteasome degradation or (d) directly to lysosomal degradation via the HSP70 complex or (e) accumulate as aggregates that can be cleared by the autophagosome (to a certain extent), at which point they (f) start playing a role in proteotoxicity-mediated cardiac dysfunction. Addendum to (c). The ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and the ubiquitin ligase (E3) act in concert to interact specifically with substrates (along with molecular chaperones) to poly-ubiquitinate the substrate, resulting in degradation by the 26S proteasome.

Figure 2.

The human HSP70 family member protein domain diversity. Of the eight HSP70 family members, three are induced by stress (indicated by *), including HSP70-1a, HSP70-1b and HSP70-6 (aka HSP72). HSC70 and HSP70-9 have localization signals and are found in the cytosol/nucleus and mitochondria, respectively [–26]. Adapted from Daugaard et al. [18].

Figure 3.

The HSP70 molecular chaperone structure and molecular pathways. (a) Structure of Hsp70. (b) The many roles the Hsp70 family of molecular chaperones has to maintain cellular proteostasis.

Figure 4.

The human HSP90 family member protein domain diversity. The inducible HSP90α is the major isoform found in the cytosol, while HSP90N, TNF receptor-associated protein 1 (TRAP1) and GRP94 are found in the plasma membrane, mitochondria and ER, respectively, as described in the text.

Figure 5.

HSP90-dependent steroid hormone receptor activation as an example of HSP90 activity. (a) The HSP90 complex is established by interactions of HSP70, HSP70-interacting protein (HIP), HSP40 and the steroid hormone receptor (SHR). (b) The SHR is transmitted via interaction with the HSP90 dimer to (c) associate with p23/IMM to change the HSP90 confirmation. Upon binding ATP, the immunophilins bind in place of the HSP70 and co-chaperones. (d) Binding of geldanamycin (a 1,4-benzoquinone ansamycin anti-tumour antibiotic that inhibits HSP90 function by binding to the ADP/ATP-binding pocket [81]) induces the disassociation of p23 and HOP, allowing the carboxyl terminus of HSC70-interacting protein (CHIP) ubiquitin ligase to attached to the complex, to poly-ubiquitinate and target it for proteasome-dependent degradation. (e) The HSP90–immunophilin–p23 complex activates SHR, which then binds steroid hormone, binds dynamitin and dynein (microtubule-associated proteins), which are then (f) trafficked along the cytoskeleton to the nucleus, where they dimerize and interact with the promoters of target genes. GA, geldamycin; SHR, steroid hormone receptor; D (in circle), ADP; T, ATP; IMM, immunofilin; D (in rhombus), dynamitin; peach circle, dynein. Adapted from [82].

Figure 6.

Structure and function of the Carboxyl terminus of HSC70-interacting protein (CHIP) encoded by the Stub1 gene. (a) The CHIP complex will recognize an Hsp70 molecular chaperone (e.g., Hsc70) that is bound to a substrate, ubiquitinate the protein substrate, and then (b) shuttle the protein to the lysosome or proteasome for degradation if CHIP is complexed with Bag-3 or Bag1, respectively. Ub, ubiquitin.

Figure 7.

Schematic of BAG-3 domains and mutations that have a potential DCM or MFM implication. Additional information on each mutation is detailed in table 2. Bold represents frameshift mutations, underlined represent deletions and italicized represent missense mutations. IPV, isoleucine–proline–valine.