Small heat shock proteins: Role in cellular functions and pathology

Abstract

Small heat shock proteins (sHsps) are conserved across species and are important in stress tolerance. Many sHsps exhibit chaperone-like activity in preventing aggregation of target proteins, keeping them in a folding-competent state and refolding them by themselves or in concert with other ATP-dependent chaperones. Mutations in human sHsps result in myopathies, neuropathies and cataract. Their expression is modulated in diseases such as Alzheimer's, Parkinson's and cancer. Their ability to bind Cu2+, and suppress generation of reactive oxygen species (ROS) may have implications in Cu2+-homeostasis and neurodegenerative diseases. Circulating αB-crystallin and Hsp27 in the plasma may exhibit immunomodulatory and anti-inflammatory functions. αB-crystallin and Hsp20 exhitbit anti-platelet aggregation: these beneficial effects indicate their use as potential therapeutic agents. sHsps have roles in differentiation, proteasomal degradation, autophagy and development. sHsps exhibit a robust anti-apoptotic property, involving several stages of mitochondrial-mediated, extrinsic apoptotic as well as pro-survival pathways. Dynamic N- and C-termini and oligomeric assemblies of αB-crystallin and Hsp27 are important factors for their functions. We propose a "dynamic partitioning hypothesis" for the promiscuous interactions and pleotropic functions exhibited by sHsps. Stress tolerance and anti-apoptotic properties of sHsps have both beneficial and deleterious consequences in human health and diseases. Conditional and targeted modulation of their expression and/or activity could be used as strategies in treating several human disorders. The review attempts to provide a critical overview of sHsps and their divergent roles in cellular processes particularly in the context of human health and disease.

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

“…However, amongst the most elusive of proteins whose structures have yet to be fully elucidated are the mammalian small heat-shock proteins (sHsps). Recent progress in this quest has, however, been significant and is summarised in a variety of review articles (Bakthisaran et al 2015;Basha et al 2012;Hochberg and Benesch 2014;Treweek et al 2015). X-ray crystallographic studies have determined the atomic-level structure of the excised α-crystallin domain (ACD) of sHsps which encompasses approximately the central 80 amino acids of the protein.…”

Serum anti-α-crystallin antibodies in women with endocrine disorders

“…Therefore, acquisition of immune tolerance would be impossible. However, recent studies have reported expression of aB-crystallin in small quantities in extraocular tissues [11], and we have proved their expression in extraocular tissues in human embryos in previous studies [21]. This could explain the tolerance to water-soluble lens antigens, of which a-crystallins are the most immunogenic [22].…”

“…It has aA-and aB-subunits. Alpha-A is abundant in eye lens and is found at low level in skeletal muscle, liver, spleen, adipose tissue, while aB-crystallin is ubiquitous, abundant in eye lens and high levels are found in heart and muscle [11]. Similar to most HSPs, a-crystallins have chaperone-like function, but aB-crystallin is also expressed in a number of pathologies, such as neurological diseases, tumours [12], infertility [13], etc.…”

“…Alpha-crystallins had long been pointed out as an example of antigens with high organ and low species specificity, which remain in an immunological isolation and present potential autoantigens. After their presence was proven in extraocular tissues [11], immunological response against them can be explained with increased aB-crystallin expression and leakage in the biological fluids due to different pathological conditions. This raises the question about the expression of aB-crystallin and immune response against it in patients with endocrine disorders linked to infertility.…”

New Insights into the Occurrence of Matrix Metalloproteases -2 and -9 in a Cohort of Breast Cancer Patients and Proteomic Correlations

“…The other subset of chaperones consists of HSPs of molecular weight less than 30 kDa (sHSPs). Among some of their functions, sHPSs participate in cell survival, cytoskeletal motility, and disruption of protein aggregation [36]. Moreover, it has been reported that the HSPs display elevated expression levels in cancer, where they may perform anti-apoptotic activities, both spontaneous and generated by therapy [37].…”