Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases

Abstract

The family of the human small Heat Shock Proteins (HSPBs) consists of ten members of chaperones (HSPB1-HSPB10), characterized by a low molecular weight and capable of dimerization and oligomerization forming large homo- or hetero-complexes. All HSPBs possess a highly conserved centrally located α-crystallin domain and poorly conserved N- and C-terminal domains. The main feature of HSPBs is to exert cytoprotective functions by preserving proteostasis, assuring the structural maintenance of the cytoskeleton and acting in response to cellular stresses and apoptosis. HSPBs take part in cell homeostasis by acting as holdases, which is the ability to interact with a substrate preventing its aggregation. In addition, HSPBs cooperate in substrates refolding driven by other chaperones or, alternatively, promote substrate routing to degradation. Notably, while some HSPBs are ubiquitously expressed, others show peculiar tissue-specific expression. Cardiac muscle, skeletal muscle and neurons show high expression levels for a wide variety of HSPBs. Indeed, most of the mutations identified in HSPBs are associated to cardiomyopathies, myopathies, and motor neuropathies. Instead, mutations in HSPB4 and HSPB5, which are also expressed in lens, have been associated with cataract. Mutations of HSPBs family members encompass base substitutions, insertions, and deletions, resulting in single amino acid substitutions or in the generation of truncated or elongated proteins. This review will provide an updated overview of disease-related mutations in HSPBs focusing on the structural and biochemical effects of mutations and their functional consequences.

High mRNA Expression Levels of Heat Shock Protein Family B Member 2 (HSPB2) Are Associated with Breast Cancer Patients’ Relapse and Poor Survival

“…HSPB2 expression is particularly elevated (despite ubiquitous expression) in cardiac and skeletal muscle [ 12 , 25 ] and was also found to be expressed in human BrCa cell lines [ 26 ]. Considering that BrCa is one of the most frequent malignancies, accounting for 11.7% of the total number of new cases diagnosed in 2020 [ 1 , 2 ] and that the role of HSPB2 in breast tumorigenesis or cancer progression has not yet been investigated, our study was focused on the potential prognostic significance of HSPB2 mRNA expression levels in BrCa patients.…”

“…Molecular chaperones, also known as heat shock proteins (HSPs) constitute a large family of molecular machines involved in the proper folding, unfolding, and assembly of polypeptides in order to maintain their structure and function [ 9 , 10 ]. In particular, HSPs curate the folding of nascent polypeptides into their native/functional configurations and prevent protein misfolding and aggregation [ 11 , 12 , 13 ]. They also target the misfolded or aggregated proteins for degradation, jointly with the protein quality control degradation machineries, i.e., the ubiquitin–proteasome system, and the autophagy–lysosome system, [ 14 ].…”

“…HSPB2 is also named myotonic dystrophy protein kinase binding protein (MKBP), because it was found to bind to the myotonic dystrophy protein kinase (DMPK), thus increasing its activity and conferring thermal protection [ 24 ]. Although it is mainly expressed in cardiac and skeletal muscle [ 12 , 25 ], the HSPB2 gene was also reported to be expressed in human breast cancer cell lines and constitutes an inhibitor of apical caspase activation in the extrinsic apoptotic pathway [ 26 ]. However, the role of HSPB2 in breast tumorigenesis remains largely obscure.…”

The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases

“…To counteract the proteotoxicity caused by misfolded proteins, these cells express—at high levels—several factors that are often redundant in their functions, which constitute the chaperone branch of the PQC system [ 25 , 26 ]. Among these, small heat shock proteins (sHSPs or HSPBs) represent a group of proteins that are specifically activated to respond to several intracellular stresses and that largely contribute to determining the fate of the misfolded proteins in terms of refolding or degradation [ 22 , 27 , 28 , 29 , 30 , 31 ]. Some HSPBs play relevant activities on MND-associated misfolded proteins; thus, this review will illustrate the importance of some HSPB family members for MN functions and their protective role against proteotoxic stresses in MNDs.…”

Heat shock protein A4 ablation leads to skeletal muscle myopathy associated with dysregulated autophagy and induced apoptosis

“…Heat shock proteins (HSPs) function as molecular chaperones to maintain cellular PQC through mediating efficient protein folding and targeting misfolded protein aggregates for degradation, and therefore have an indispensable role for proper myogenesis [ 8 – 12 ]. Mutations in human HSPs have been identified in patients with muscle myopathy [ 13 – 15 ].…”