sHSPs Function Research Articles

Small heat shock proteins as modulators of cell death in Plasmodium falciparum parasites and its human host

Plasmodium falciparum, the predominant cause of severe malaria, thrives within both poikilotherm mosquitoes and homeotherm humans, navigating challenging temperature shifts during its life cycle. Survival in such varying environments necessitate the development of robust mechanisms, including a sophisticated protein folding system to mitigate proteopathy. The parasite needs to control the survival of its host cells which affects its chances of development and propagation. Central to this system are heat shock proteins (Hsps), among which small Hsps (sHsps) play pivotal roles in maintaining proteostasis (protein homeostasis). In both humans and P. falciparum, numerous sHsps have been identified, making them attractive candidates as biomarkers for diagnostic and drug development strategies. Evidence is accumulating suggesting that these sHsps participate in cell death processes, potentially influencing disease pathogenesis. Despite their significance, the precise functions of sHsps in P. falciparum’s adaptation to stress conditions remains largely unknown. Comparative structural analysis of sHsps between human and P. falciparum reveals species-specific variations. Despite conserved tertiary structures, unique motifs are found in parasite sHsps which may modulate specialised chaperone functions. This review discusses the conserved and distinctive motifs of sHsps from the human host and the parasite, offering insights into shared and unique attributes. These findings illuminate the potential for species-specific targeting of sHsps, as players in cell death processes that may foster innovative biomarker identification approaches. As malaria continues to ravage Sub-Saharan Africa, understanding the molecular intricacies guiding parasite survival are essential in the development of interventions with heightened efficacy against this global health crisis.

A small heat shock protein GmHSP18.5a improves the male fertility restorability of cytoplasmic male sterility-based restorer line under high temperature stress in soybean

Small heat shock protein (sHSP) is involved in high temperature (HT) stress response. However, the function of sHSPs in regulating male fertility of soybean under HT stress remains largely unknown. Here, we identified a sHSP gene, GmHSP18.5a, which was responded to HT stress during flowering in cytoplasmic male sterility (CMS)-based restorer line of soybean. Moreover, GmHSFA6b turned out to directly activated the expression of GmHSP18.5a by binding to the heat shock cis-element in its promoter. Overexpression of GmHSP18.5a increased male fertility in transgenic Arabidopsis, soybean CMS-based restorer line and its hybrid F1 with CMS line under HT stress. Reactive oxygen species (ROS) content detection revealed that GmHSP18.5a promoted the ROS scavenging ability of Arabidopsis inflorescence and soybean flower bud under HT stress. Enzyme activity assay and gene expression analysis indicated that GmHS18.5a mainly increased the activity of antioxidant enzymes and the expression level of ROS metabolism-related genes under HT stress. Our results indicated that GmHSP18.5a improved the male fertility restorability of CMS-based restorer line in soybean by regulating ROS metabolic pathway and reducing ROS accumulation. Our findings not only revealed the molecular mechanism of sHSP regulating the male fertility of soybean under HT stress, but also provided a theoretical basis for creating strong restorer line with thermotolerance.

Functional Diversity of Mammalian Small Heat Shock Proteins: A Review.

The small heat shock proteins (sHSPs), whose molecular weight ranges from 12∼43 kDa, are members of the heat shock protein (HSP) family that are widely found in all organisms. As intracellular stress resistance molecules, sHSPs play an important role in maintaining the homeostasis of the intracellular environment under various stressful conditions. A total of 10 sHSPs have been identified in mammals, sharing conserved α-crystal domains combined with variable N-terminal and C-terminal regions. Unlike large-molecular-weight HSP, sHSPs prevent substrate protein aggregation through an ATP-independent mechanism. In addition to chaperone activity, sHSPs were also shown to suppress apoptosis, ferroptosis, and senescence, promote autophagy, regulate cytoskeletal dynamics, maintain membrane stability, control the direction of cellular differentiation, modulate angiogenesis, and spermatogenesis, as well as attenuate the inflammatory response and reduce oxidative damage. Phosphorylation is the most significant post-translational modification of sHSPs and is usually an indicator of their activation. Furthermore, abnormalities in sHSPs often lead to aggregation of substrate proteins and dysfunction of client proteins, resulting in disease. This paper reviews the various biological functions of sHSPs in mammals, emphasizing the roles of different sHSPs in specific cellular activities. In addition, we discuss the effect of phosphorylation on the function of sHSPs and the association between sHSPs and disease.

Growth-enhancing effect of bacterial and plant heat shock proteins in Escherichia coli

Heat shock proteins (Hsps) are frequent targets to be manipulated in Escherichia coli (E. coli) to improve the production of recombinant proteins and secondary metabolites for industrial applications. In this study, we examined if the heterologous expression of eukaryotic Hsps can effectively enhance bacterial growth, compared to overexpression of endogenous bacterial Hsps. Five transgenic E. coli cell lines (TCs), individually expressing recombinant bacterial Hsps (IbpA, IbpB, and DnaK) and plant Hsps [carrot (Daucus carota L.: Dc) Hsp17.7 and Hsp70], were generated to compare the growth-enhancing effect of each protein. Under normal and heat conditions, the TC expressing DcHsp17.7 showed the highest growth rate and maximum cell density. Under cold, acetate, and ethanol conditions, the TC overexpressing IbpA showed the highest growth rate. TCs expressing Hsps showed higher protein levels than the control. The amino acid sequence comparison shows that bacterial and plant small(s) Hsps are less conserved than larger Hsp70s. Conserved 13 a.a. sequences in the N-terminal domain of plant sHsps were not present in the bacterial IbpA and IbpB, suggesting possible differences in the functions of plant and bacterial sHsps. Results show that different Hsps could be employed to maximize bacterial cell growth for varied industrial applications.

Protective effects of small heat shock proteins in Daphnia magna against heavy metal exposure

Daphnia magna is one of the most commonly used model organisms to assess toxicity of heavy metal and other xenobiotics. However, the lack of knowledge about important stress-resistant molecules limits our understanding of the alteration of phenotypic and physiological traits of D. magna upon stress exposures. In this study, we focused on a chaperone family of small heat shock protein (sHSP) that has been found in archaea, bacteria and eukaryotes and plays an important role in stress tolerance. A total of eleven sHSP genes (termed DmsHSP1 - DmsHSP11) were identified from the D. magna genome, whose expression profiles during exposure to heavy metal (Cd2+, Cu2+ and Zn2+) and a few other potential pollutants were evaluated via qRT-PCR and RNA-Seq analysis. The results highlighted the predominant role of DmsHSP1 with the highest basal expression level in adults and robust upregulation upon exposure to heavy metals (Cu2+ > Cd2+ > Zn2+). In vivo, recombinant protein rDmsHSP1–21 and rDmsHSP11–12.8 could not only prevent model substrates agglutination induced by heavy metals or reducer dithiotreitol (DTT), but also protect tissue proteins and enzymes from denaturation and inactivation caused by heavy metals or high temperature. Ectopically expression of DmsHSP1–21 or DmsHSP11–12.8 in E. coli conferred host enhanced resistance against various abiotic stresses including Cd2+, Cu2+ and phenazine methosulfate (PMS). Knockdown of DmsHSP1–21 by RNAi, but not for DmsHSP11–12.8, significantly increased the vulnerability of D. magna to heavy metal exposure. Our work provides systematic information on the evolution and function of sHSPs in D. magna and leads to important insights into the mechanisms by which D. magna survive in adverse environments.

Differential Roles of Three α-Crystallin Domain-Containing sHsps of Beauveria bassiana in Asexual Development, Multiple Stress Tolerance and Virulence.

Small heat shock proteins (sHsps) containing conserved α-crystallin domain play important roles in many cellular processes, but little is known about the functions of sHsps in filamentous entomopathogens. Here, three sHsps of Hsp20, Hsp30a, and Hsp30b were characterized in Beauveria bassiana, a filamentous fungal insect pathogen that serves as the main source of wide-spectrum fungal insecticides. The results demonstrated that these three genes are interrelated at the transcriptional level under normal and heat-shocked conditions. Meanwhile, all the deletion mutants showed significant but differential changes in cell wall integrity, antioxidant activity, hyphal tolerance to carbendazim fungicide, conidial tolerance to 45 °C wet heat and virulence. However, only Δhsp30b showed growth defects on rich and minimal media at 25 °C and Δhsp30a displayed the reduction in conidiophores and conidia. Moreover, the single deletion of hsp30a and hsp30b caused the decreases in hyphal growth at 34 °C and conidial tolerance to UV-B irradiation. Our findings provide a global insight into vital roles of hsp20, hsp30a, and hsp30b in asexual development, environmental adaptation, and fungal virulence of B. bassiana.

Assessing the Importance of Chloroplast and Mitochondrial Small Heat Shock Proteins in Arabidopsis thaliana

Organisms have a dedicated class of proteins to safeguard their proteome – molecular chaperones. Many chaperones help proteins fold and unfold, maintain their structure, and even re‐fold denatured protein aggregates by using ATP. Small heat shock proteins (sHSPs) are ATP‐independent chaperones that are proposed to prevent irreversible aggregation of denaturing proteins and handing them off to the ATP‐dependent chaperones. sHSPs are especially diverse in plants, possibly due to the exposure of plants to environmental stress due to their sessile nature. Despite their widespread occurrence, little is known about the exact function and role of sHSPs, especially in chloroplasts and mitochondria. Both organelles are critical to plant growth, development and reproduction and are also sources of cellular stress via production of reactive oxygen species. Understanding the role of sHSPs in these organelles is vital to grasp how plants deal with stress and could allow for transferring this knowledge into crop plants to improve agricultural yield. The model plant Arabidopsis thaliana possesses four sHSPs localized to the chloroplasts and mitochondria. HSP23.5‐MI/CP and HSP23.6‐MI/CP are thought to dual‐localize to both organelles, HSP25.3‐CP localizes to chloroplasts and HSP26.5‐MII is targeted to mitochondria. These sHSPs are primarily expressed under heat stress conditions. We have developed single, double, triple and quadruple knockout mutants of these four organelle sHSPs and confirmed that they are protein nulls by immunoblotting with specific antisera. Under standard growth conditions these organelle sHSPs appear dispensable, as the knockout mutants grow similarly to wild type. Notably, the organelle sHSP mutant plants show only minimal growth defects when heat stressed, which is in stark contrast to a lethal phenotype shown by a null mutant of the ATP‐dependent chaperone HSP101. Further work is in progress to determine if chaperones or other proteins are altered in expression to compensate for absence of the sHSPs during stress. Additionally, the dual‐localization of HSPs 23.5‐MI/CP and 23.6‐MI/CP has yet to be fully established and also raises the question of crosstalk between chloroplast and mitochondrial sHSPs. To answer these questions a combination of immunoblotting and proteomics approach on isolated chloroplasts and mitochondria is being taken.

Small Heat Shock Proteins in Retinal Diseases.

This review summarizes the latest findings on small heat shock proteins (sHsps) in three major retinal diseases: glaucoma, diabetic retinopathy, and age-related macular degeneration. A general description of the structure and major cellular functions of sHsps is provided in the introductory remarks. Their role in specific retinal diseases, highlighting their regulation, role in pathogenesis, and possible use as therapeutics, is discussed.

A Nodule-Localized Small Heat Shock Protein GmHSP17.1 Confers Nodule Development and Nitrogen Fixation in Soybean

Small heat shock proteins (sHSPs) are ubiquitous proteins present in all organisms. The sHSPs are not only upregulated under heat shock as well as other stresses but also are expressed in unstressed cells, indicating quite diverse functions of sHSPs. However, there is little known about the role of sHSPs in nodulation and nitrogen fixation in soybean. In this study, we cloned a candidate protein of sHSP, GmHSP17.1, from proteome of nodule and analyzed its function in soybean nodulation. We found that GmHSP17.1 was a cytosolic protein and preferentially expressed during nodule development. An overexpression of GmHSP17.1 in composite transgenic plants showed increases in nodule number, fresh weight, nodule size, area of infection cells, and nitrogenase activity, and subsequently promoted the content of nitrogen and growth of soybean plants. While GmHSP17.1 RNA interference (RNAi) lines showed significantly impaired nodule development and nitrogen fixation efficiency. Through liquid chromatography-tandem mass spectrometry (LC-MS/MS), GmRIP1 was identified as the first potential target of GmHSP17.1, and was shown to be specifically expressed in soybean nodules. The interaction between GmHSP17.1 and GmRIP1 was further confirmed by yeast-two hybrid (Y2H), bimolecular fluorescence complementation (BiFC) in vivo and pull-down assay in vitro. Furthermore, peroxidase activity was markedly increased in GmHSP17.1 overexpressed nodules and decreased in RNAi lines. As a result, the reactive oxygen species (ROS) content greatly decreased in GmHSP17.1 overexpression lines and increased in suppression lines. Taken together, we conclude that GmHSP17.1 plays an important role in soybean nodulation through interacting with GmRIP1. Our results provide foundation for studying the mechanism of nitrogen fixation and for the genetics improvement of legume plants.

Role of ATP-Small Heat Shock Protein Interaction in Human Diseases.

Adenosine triphosphate (ATP) is an important fuel of life for humans and Mycobacterium species. Its potential role in modulating cellular functions and implications in systemic, pulmonary, and ocular diseases is well studied. Plasma ATP has been used as a diagnostic and prognostic biomarker owing to its close association with disease’s progression. Several stresses induce altered ATP generation, causing disorders and illnesses. Small heat shock proteins (sHSPs) are dynamic oligomers that are dominantly β-sheet in nature. Some important functions that they exhibit include preventing protein aggregation, enabling protein refolding, conferring thermotolerance to cells, and exhibiting anti-apoptotic functions. Expression and functions of sHSPs in humans are closely associated with several diseases like cataracts, cardiovascular diseases, renal diseases, cancer, etc. Additionally, there are some mycobacterial sHSPs like Mycobacterium leprae HSP18 and Mycobacterium tuberculosis HSP16.3, whose molecular chaperone functions are implicated in the growth and survival of pathogens in host species. As both ATP and sHSPs, remain closely associated with several human diseases and survival of bacterial pathogens in the host, therefore substantial research has been conducted to elucidate ATP-sHSP interaction. In this mini review, the impact of ATP on the structure and function of human and mycobacterial sHSPs is discussed. Additionally, how such interactions can influence the onset of several human diseases is also discussed.

Investigating the non‐cell autonomous role of glial chaperones in Alzheimer’s disease

AbstractBackgroundAstrocytes are vital in the onset and progression of Alzheimer’s disease (AD). Accumulation of reactive astrocytes, together with tau phosphorylation, correlates very strongly with cognitive decline.Molecular chaperones are essential for maintaining protein homeostasis. One family of chaperones are the small heat shock proteins (sHSPs), which include HSPB1 and CRYAB. Expression of these sHSPs seems to be restricted to glial cells, and levels are found to increase in those astrocytes found in AD brains. The role that sHSP play in astrocytes in AD is still not known. Emerging evidence suggests vital interplay between different cell types during neurodegenerative diseases. We therefore aim to investigate the non‐cell autonomous role of astrocytic sHSPs in AD.MethodWe are using primary mouse neurons and organotypic brain slice cultures in conjunction with the recombinant adeno‐associated viral system (rAAV). These systems will allow us to replicate the tau pathology found in AD, investigate neuron‐astrocyte interactions and determine whether either can be altered by overexpression of our sHSPs.Using immunofluorescence, confocal microscopy and western blotting we are characterising expression and localization of sHSPs in post‐mortem human AD brain tissue and brain slice cultures.ResultOur data shows that HSPB1 is specifically expressed in astrocytes in both human brain tissue and slice cultures. Interestingly, HSPB1 levels in the human brain increase in GFAP‐positive astrocytes surrounding amyloid plaques. When organotypic brain slices are treated with cytokines or Aβ oligomers, reactive astrocytes are induced and levels of HSPB1 and CRYAB are also increased, similar to what we observe in human AD brain.ConclusionOur results in human AD brain highlight the importance of astrocytic HSPB1 in AD, and we provide evidence to suggest not only that organotypic brain slices are a good model to replicate and study the function of sHSPs in AD, but that HSPB1 and CRYAB play an important role in the response to AD‐relevant pathology.Using rAAVs, we aim to manipulate astrocytic sHSPs levels in organotypic brain slices to investigate whether astrocytic sHSPs could modulate neuronal health and tau pathology in a non‐cell autonomous manner.

Novel self-regulation strategy of a small heat shock protein for prodigious and rapid expression on demand.

In this mini-review, we summarize the known and novel regulation mechanisms of small heat shock proteins (sHsps). sHsps belong to a well-conserved family of ATP-independent oligomeric chaperones that protect denatured proteins from forming irreversible aggregates by co-aggregation. The functions of sHsps as a first line of defense against acute stresses require the high abundance of sHsps on demand. The heat stress-induced expression of IbpA, one of the sHsps in Escherichia coli, is regulated by σ32, an RNA polymerase subunit, and the thermoresponsive mRNA structures in the 5' untranslated region, called RNA thermometers. In addition to the known mechanisms, a recent study has revealed unexpected processes by which the oligomeric IbpA self-represses the ibpA translation via the direct binding of IbpA to its own mRNA, and mediates the mRNA degradation. In summary, the role of IbpA as an aggregation-sensor, combined with other mechanisms, tightly regulates the expression level of IbpA, thus enabling the sHsp to function as a "sequestrase" upon acute aggregation stress, and provides new insights into the mechanisms of other sHsps in both bacteria and eukaryotes.

Elucidation of Diverse Physico-Chemical Parameters in Mammalian Small Heat Shock Proteins: A Comprehensive Classification and Structural and Functional Exploration Using In Silico Approach.

Small heat shock proteins (sHSPs), often known as molecular chaperones, are most prevalent in nature. Under certain stress-induced conditions, these sHSPs act as an ATP-independent variation and thus prevent the inactivation of various non-native substrate proteins and their aggregation. They also assist other ATP-dependent chaperones in the refolding of these substrates. In the case of prokaryotes and lower eukaryotes, the chaperone functions of sHSPs can bind a wide range of cellular proteins but preferentially protect translation-related proteins and metabolic enzymes. Eukaryotes usually encode a larger number of sHSPs than those of prokaryotes. The chaperone functions of mammalian sHSPs are regulated by phosphorylation in cells and also by temperature. Their sHSPs have different sub-cellular compartments and cell/tissue specificity. The substrate proteins of mammalian sHSPs or eukaryotic sHSPs accordingly reflect their multi-cellular complexity. The sHSPs of animals play roles in different physiological processes as cell differentiation, apoptosis, and longevity. In this work, the characterization, location, tissue specificity, and functional diversity of sHSPs from seven different mammalian species with special emphasis on humans have been studied. Through this extensive work, a novel and significant attempt have been made to classify them based on their omnipresence, tissue specificity, localization, secondary structure, probable mutations, and evolutionary significance.

The Chloroplastic Small Heat Shock Protein Gene KvHSP26 Is Induced by Various Abiotic Stresses in Kosteletzkya virginica.

Small heat shock proteins (sHSPs) are a group of chaperone proteins existed in all organisms. The functions of sHSPs in heat and abiotic stress responses in many glycophyte plants have been studied. However, their possible roles in halophyte plants are still largely known. In this work, a putative sHSP gene KvHSP26 was cloned from K. virginica. Bioinformatics analyses revealed that KvHSP26 encoded a chloroplastic protein with the typical features of sHSPs. Amino acid sequence alignment and phylogenetic analysis demonstrated that KvHSP26 shared 30%-77% homology with other sHSPs from Arabidopsis, cotton, durian, salvia, and soybean. Quantitative real-time PCR (qPCR) assays exhibited that KvHSP26 was constitutively expressed in different tissues such as leaves, stems, and roots, with a relatively higher expression in leaves. Furthermore, expression of KvHSP26 was strongly induced by salt, heat, osmotic stress, and ABA in K. virginica. All these results suggest that KvHSP26 encodes a new sHSP, which is involved in multiple abiotic stress responses in K. virginica, and it has a great potential to be used as a candidate gene for the breeding of plants with improved tolerances to various abiotic stresses.

Molecular cloning and expression patterns of two small heat shock proteins from Chilo suppressalis (Walker)

Small heat shock proteins (sHSPs) are a very complex protein superfamily that increase insect temperature tolerance. In order to deeply understand the function and role of sHSPs in Chilo suppressalis (Walker), this study isolated and identified two CsHSP genes lacking introns from C. suppressalis, Cshsp23.9 and Cshsp27.3. The cDNA full-length of Cshsp23.9 and Cshsp27.3 were 909 and 1 036 bp encoding 220 and 242 amino acids, respectively. Alignment with homologs and phylogenetic analysis indicated Cshsp23.9 and Cshsp27.3 were two new types of Cshsps in C. suppressalis. Real-time quantitative PCR (qPCR) revealed that Cshsp23.9 had the highest relative expression in hindgut compared with other tissues (head, epidermis, foregut, midgut, fat body, Malpighian tubules, and hemocytes), while Cshsp27.3 expressed the highest in fat body content. When exposed to thermal stress from −11 to 43°C for 2 h, two genes showed different expression patterns. Cshsp23.9 did not respond to low temperature, but could be up-regulated by high temperature and the highest expression temperature was at 36°C. Cshsp27.3 could only be induced by mild temperature, with the highest expression at 15 and 30°C. In conclusion, Cshsp23.9 and Cshsp27.3 existed in different tissues/organs of C. suppressalis, and played different important roles in C. suppressalis to resist temperature stress and regulate physiological activities.

Structural and functional properties of proteins interacting with small heat shock proteins.

Small heat shock proteins (sHsps) are ubiquitous molecular chaperones found in all domains of life, possessing significant roles in protein quality control in cells and assisting the refolding of non-native proteins. They are efficient chaperones against many in vitro protein substrates. Nevertheless, the in vivo native substrates of sHsps are not known. To better understand the functions of sHsps and the mechanisms by which they enhance heat resistance, sHsp-interacting proteins were identified using affinity purification under heat shock conditions. This paper aims at providing some insights into the characteristics of natural substrate proteins of sHsps. It seems that sHsps of prokaryotes, as well as sHsps of some eukaryotes, can bind to a wide range of substrate proteins with a preference for certain functional classes of proteins. Using Drosophila melanogaster mitochondrial Hsp22 as a model system, we observed that this sHsp interacted with the members of ATP synthase machinery. Mechanistically, Hsp22 interacts with the multi-type substrate proteins under heat shock conditions as well as non-heat shock conditions.

Peeking from behind the veil of enigma: emerging insights on small heat shock protein structure and function.

This is a short paper on new ways to think about the structure and function of small heat shock proteins (sHSPs), perhaps the most enigmatic family among protein chaperones. The goal is to incorporate new observations regarding the disordered regions of small heat shock proteins (sHSPs) into the large body of structural information on the conserved structural alpha-crystallin domains (ACD) that define the sHSP family. Disordered regions (N-terminal region and C-terminal region or NTR and CTR, respectively) represent over 50% of the sHSP sequence space in the human genome and are refractory to traditional structural biology approaches, posing a roadblock on the path towards a mechanistic understanding of how sHSPs function. A model in which an ACD dimer serves as a template that presents three grooves into which other proteins or other segments of sHSPs can bind is presented. Short segments within the disordered regions are observed to bind into the ACD grooves. There are more binding segments than there are grooves, and each binding event is weak and transient, creating a dynamic equilibrium of tethered and untethered disordered regions. The ability of an NTR to be in dynamic equilibrium between tethered/sequestered and untethered states suggests several mechanistic alternatives that need not be mutually exclusive. New ways of thinking about (and approaching) the intrinsic properties of sHSPs may finally allow the veil of enigma to be removed from sHSPs.

The effect of hyperbaric oxygen on mitochondrial and glycolytic energy metabolism: the caloristasis concept.

We present new data on the effects of HBOT on human kidney (HK-2) cell metabolism using a SeaHorse XF Analyzer to evaluate separately the state of mitochondrial and glycolytic energy metabolism. The data are discussed in the context of the concept of cellular caloristasis networks. The information on the changes in cellular energy metabolism stimulated by HBOT presented here provides new insights into the cellular energy state and mitochondrial environment in which sHSPs function. These data will be useful in forming testable hypotheses about the functions of translocated sHSPs in human mitochondria responding to stressors.

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

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.

Small heat shock proteins: multifaceted proteins with important implications for life.

Small Heat Shock Proteins (sHSPs) evolved early in the history of life; they are present in archaea, bacteria, and eukaryota. sHSPs belong to the superfamily of molecular chaperones: they are components of the cellular protein quality control machinery and are thought to act as the first line of defense against conditions that endanger the cellular proteome. In plants, sHSPs protect cells against abiotic stresses, providing innovative targets for sustainable agricultural production. In humans, sHSPs (also known as HSPBs) are associated with the development of several neurological diseases. Thus, manipulation of sHSP expression may represent an attractive therapeutic strategy for disease treatment. Experimental evidence demonstrates that enhancing the chaperone function of sHSPs protects against age-related protein conformation diseases, which are characterized by protein aggregation. Moreover, sHSPs can promote longevity and healthy aging in vivo. In addition, sHSPs have been implicated in the prognosis of several types of cancer. Here, sHSP upregulation, by enhancing cellular health, could promote cancer development; on the other hand, their downregulation, by sensitizing cells to external stressors and chemotherapeutics, may have beneficial outcomes. The complexity and diversity of sHSP function and properties and the need to identify their specific clients, as well as their implication in human disease, have been discussed by many of the world's experts in the sHSP field during a dedicated workshop in Québec City, Canada, on 26-29 August 2018.