Small Heat Shock Protein Research Articles

Structural characterization and functional analysis of human αB-crystallin with the p.R11G mutation: Insights into cataractogenesis and cardiomyopathy.

Structural characterization and functional analysis of human αB-crystallin with the p.R11G mutation: Insights into cataractogenesis and cardiomyopathy.

DSP-1, the major fibronectin type-II protein of donkey seminal plasma is a small heat-shock protein and exhibits chaperone-like activity against thermal and oxidative stress.

DSP-1, the major fibronectin type-II protein of donkey seminal plasma is a small heat-shock protein and exhibits chaperone-like activity against thermal and oxidative stress.

Small Heat Shock Proteins: Protein Aggregation Amelioration and Neuro- and Age-Protective Roles.

Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging.

Small heat shock proteins as relevant biomarkers for anthropogenic stressors in earthworms

Small heat shock proteins as relevant biomarkers for anthropogenic stressors in earthworms

RNA Interference Targeting Small Heat Shock Protein B8 Failed to Improve Distal Hereditary Motor Neuropathy in the Mouse Model.

Missense mutations in the HSPB8 gene, encoding the small heat shock protein B8, cause distal hereditary motor neuropathy (dHMN) or an axonal form of Charcot-Marie-Tooth disease (CMT subtype 2L). Mice expressing mutant Hspb8 (Lys141Asn) mimic the human disease, whereas mice lacking Hspb8 show no overt phenotype. We aimed to design an RNA interference treatment strategy that rescues the mutant HSPB8 neuronal and muscle phenotype in patient-derived motor neurons and in a knock-in mouse model of CMT2L/dHMN. We optimized RNA interference sequences targeting both human HSPB8 and mouse HspB8 transcripts with the aim to alleviate disease symptoms. We used human induced pluripotent stem cells and the Hspb8 knock-in mouse model. We designed lenti- and adeno-associated viral vectors that contained the short-hairpin RNA constructs. We performed expression and microscopy studies, magnetic resonance imaging, behaviour analysis and electrophysiology. In CMT2L patient-derived induced pluripotent stem cells differentiated towards motor neurons, reducing the HSPB8 expression with a short-hairpin RNA (shRNA), directed towards the 3' untranslated region (3'UTR), ameliorated the morphology and fragmentation of mitochondria. The AAV9-mediated treatment of the 3'UTR shRNA construct, under neuron-specific regulation, in Hspb8 knock-in mice showed inconclusive results towards functional improvement upon expression studies, magnetic resonance imaging and neuropathological findings. Given the limited beneficial effect of the treatment, the RNA interference-mediated reduction of HSPB8/Hspb8 expression might not be the best therapeutic strategy to treat dHMN/CMT2L, unless a higher viral load and earlier treatment can be applied to the mouse model.

Molecular cloning, expression profiling and functional characterization of three small heat shock protein genes in Sogatella furcifera reveals their roles in heat tolerance

Molecular cloning, expression profiling and functional characterization of three small heat shock protein genes in Sogatella furcifera reveals their roles in heat tolerance

Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation.

ATP-independent chaperones facilitate clearance of aggregated proteins through autophagy. This study provides insight into the molecular mechanism by which small heat shock proteins interact with the aggregation-prone low complexity protein domains of RNA-binding proteins linked to neurodegenerative disease pathologies. The results provide a foundation for designing improved chaperones as therapeutics and illustrate a methodology to identify regions in low complexity domains for targeted drug development in the context of neurodegenerative disease.

Current insights into molecular mechanisms of environmental stress tolerance in Cyanobacteria.

The photoautotrophic nature of cyanobacteria, coupled with their fast growth and relative ease of genetic manipulation, makes these microorganisms very promising factories for the sustainable production of bio-products from atmospheric carbon dioxide. However, both in nature and in cultivation, cyanobacteria go through different abiotic stresses such as high light (HL) stress, heavy metal stress, nutrient limitation, heat stress, salt stress, oxidative stress, and alcohol stress. In recent years, significant improvement has been made in identifying the stress-responsive genes and the linked pathways in cyanobacteria and developing genome editing tools for their manipulation. Metabolic pathways play an important role in stress tolerance; their modification is also a very promising approach to adapting to stress conditions. Several synthetic as well as systems biology approaches have been developed to identify and manipulate genes regulating cellular responses under different stresses. In this review, we summarize the impact of different stresses on metabolic processes, the small RNAs, genes and heat shock proteins (HSPs) involved, changes in the metabolome and their adaptive mechanisms. The developing knowledge of the adaptive behaviour of cyanobacteria may also be utilised to develop better stress-responsive strains for various applications.

Heat shock protein 22: A new direction for cardiovascular disease (Review).

Small heat shock proteins (sHSPs) are common molecular chaperone proteins that function in various biological processes, and serve indispensable roles in maintaining cellular protein homeostasis and regulating the hydrolysis of unfolded proteins. HSP22 is a member of the sHSP family that is primarily expressed in the heart and skeletal muscle, as well as in various types of cancer. There have been important findings concerning the role of HSP22 in cardiovascular diseases. The aim of the present study was to provide insights into the various molecular mechanisms by which HSP22 functions in the heart, including oxidative stress, autophagy, apoptosis, the subcellular distribution of proteins and the promoting effect of proteasomes. In addition, drugs and cytokines, including geranylgeranylacetone, can exert protective effects on the heart by regulating the expression of HSP22. Based on increasingly abundant research, HSP22 may be considered a potential therapeutic target in cardiovascular diseases.

The Hsf1-sHsp cascade has pan-antiviral activity in mosquito cells

Aedes mosquitoes transmit pathogenic arthropod-borne (arbo) viruses, putting nearly half the world’s population at risk. Blocking virus replication in mosquitoes is a promising approach to prevent arbovirus transmission, the development of which requires in-depth knowledge of virus-host interactions and mosquito immunity. By integrating multi-omics data, we find that heat shock factor 1 (Hsf1) regulates eight small heat shock protein (sHsp) genes within one topologically associated domain in the genome of the Aedes aegypti mosquito. This Hsf1-sHsp cascade acts as an early response against chikungunya virus infection and shows pan-antiviral activity against chikungunya, Sindbis, and dengue virus as well as the insect-specific Agua Salud alphavirus in Ae. aegypti cells and against chikungunya virus and O’nyong-nyong virus in Aedes albopictus and Anopheles gambiae cells, respectively. Our comprehensive in vitro data suggest that Hsf1 could serve as a promising target for the development of novel intervention strategies to limit arbovirus transmission by mosquitoes.

MitoStores: stress-induced aggregation of mitochondrial proteins.

Most mitochondrial proteins are synthesized in thecytosol and post-translationally imported into mitochondria. If the rate of protein synthesis exceeds the capacity of themitochondrial import machinery, precursor proteins can transiently accumulate in the cytosol. The cytosolic accumulation of mitochondrial precursors jeopardizes cellular protein homeostasis (proteostasis) and can be the cause of diseases. Inorder to prevent these toxic effects, most non-imported precursors are rapidly degraded by the ubiquitin-proteasome system. However, cells employ a second layer of defense which is the facilitated sequestration of mitochondrial precursor proteins in transient protein aggregates. The formation of such structures is triggered by nucleation factors such as small heat shock proteins. Disaggregases and chaperones can liberate precursors from cytosolic aggregates to pass them on to the mitochondrial import machinery or, under persistent stress conditions, to the proteasome for degradation. Owing to their role as transient buffering systems, these aggregates were referred to as MitoStores. This review articles provides a general overview about the MitoStore concept and the early stages in mitochondrial protein biogenesis in yeast and, in cases where aspects differ, in mammalian cells.

XopAE Effector from Xanthomonas phaseoli pv. manihotis Targets HSP20-Like p23 Cochaperone to Suppress Plant Basal Immunity.

Pathogenic bacteria use Type 3 effector proteins to manipulate host defenses and alter metabolism to favor their survival and spread. The non-model bacterial pathogen Xanthomonas phaseoli pv. manihotis (Xpm) causes devastating disease in cassava. The molecular role of Type 3 effector proteins from Xpm in causing disease is largely unknown. Here, we report that the XopAE effector from Xpm suppresses plant defense responses. Our results showed that XopAE is a suppressor of basal defenses such as callose deposition and the production of reactive oxygen species (ROS). XopAE targets a small heat shock protein (Mep23-1 cochaperone) in cassava and its homolog Atp23-1 in Arabidopsis. XopAE localizes to the nucleus and in scattered points throughout the cell border, while Mep23-1 shows a nucleocytoplasmic localization. Upon interaction, XopAE hijacks Mep23-1 to the scattered points throughout the cell border and they also interact in nucleus. Our results indicate that the interaction between XopAE and Mep23-1 is essential for suppressing basal plant defense. This study is one of the first to address the molecular mechanisms deployed by Xpm to cause disease in cassava, a non-model crop plant.

Key Role of Phosphorylation in Small Heat Shock Protein Regulation via Oligomeric Disaggregation and Functional Activation.

Heat shock proteins (HSPs) are essential molecular chaperones that protect cells by aiding in protein folding and preventing aggregation under stress conditions. Small heat shock proteins (sHSPs), which include members from HSPB1 to HSPB10, are particularly important for cellular stress responses. These proteins share a conserved α-crystallin domain (ACD) critical for their chaperone function, with flexible N- and C-terminal extensions that facilitate oligomer formation. Phosphorylation, a key post-translational modification (PTM), plays a dynamic role in regulating sHSP structure, oligomeric state, stability, and chaperone function. Unlike other PTMs such as deamidation, oxidation, and glycation-which are often linked to protein destabilization-phosphorylation generally induces structural transitions that enhance sHSP activity. Specifically, phosphorylation promotes the disaggregation of sHSP oligomers into smaller, more active complexes, thereby increasing their efficiency. This disaggregation mechanism is crucial for protecting cells from stress-induced damage, including apoptosis, inflammation, and other forms of cellular dysfunction. This review explores the role of phosphorylation in modulating the function of sHSPs, particularly HSPB1, HSPB4, and HSPB5, and discusses how these modifications influence their protective functions in cellular stress responses.

Revival of the Escherichia coli heat shock response after two decades with a small Hsp in a critical but distinct act.

The heat stress response is an essential defense mechanism in all organisms. Heat shock proteins (Hsps) are produced in response to thermal stress, with their expression levels regulated by heat shock transcription factors. In Escherichia coli, the key transcription factor σ32 positively regulates Hsp expression. Studies from over two decades ago revealed that σ32 abundance is negatively controlled under normal conditions, mainly through degradation mechanisms involving DnaK, GroEL, and FtsH. Beyond this established mechanism, recent findings indicate that a small heat shock protein IbpA also plays a role in the translational regulation of σ32, adding a new layer to the established model. This review highlights the role of a new actor, IbpA, which strongly suppresses σ32 expression under non-stress conditions and markedly increases it during heat shock.

Insights into small Heat Shock Proteins: Drivers of environmental stress tolerance in selected animal species

Insects, nematodes, and aquatic animals face several biotic and abiotic stressors that can significantly affect their fitness – specifically damaging their cellular protein function. As a result, they have evolved sophisticated stress-responsive mechanisms. Certain endogenous proteins, the small Heat Shock Proteins (sHSPs), are proposed to maintain the stability and function of proteins under stress. Since the identification of the first sHSPs, an increasing number of sHSPs, mainly due to the new robust sequencing tools, continue to be identified and reported to play a critical role in the response of organisms to stress. This review explores and summarizes the contributions of the sHSPs implicated in the stress response of different animal species in unique environments. Understanding their function is crucial for advancing our knowledge of how different animal species adapt to harsh environments while maintaining cellular homeostasis.

Transcription factor TCF7L1 targeting HSPB6 is involved in EMT and PI3K/AKT/mTOR pathways in bladder cancer

Bladder cancer is notorious for its high recurrence and costly treatment burden, prompting a search for novel therapeutic targets. Our study focuses on HSPB6, a small heat shock protein whose reduced expression in bladder cancer suggests a role in tumor biology. Using an integrative approach of bioinformatics, RNA sequencing, and cell-based assays, we show that HSPB6 upregulation inhibits cancer cell proliferation and metastasis, while promoting apoptosis. Moreover, TCF7L1-mediated upregulation of HSPB6 leads to suppression of the PI3K/AKT/mTOR signaling pathway, a key driver of cancer progression. These results position HSPB6 as a compelling target for bladder cancer therapy, and its regulatory role in the PI3K/AKT/mTOR axis underscores its therapeutic potential. Our findings pave the way for future investigations into HSPB6-centered treatment strategies.

Interaction of small heat shock proteins with BAG3.

Interaction of small heat shock proteins with BAG3.

Two sides of the same coin: heat shock proteins as biomarkers and therapeutic targets for some complex diseases.

Heat shock proteins are molecular chaperones that play crucial roles in the folding and unfolding of complex polypeptides within the cellular system. These molecules are involved in various processes, including vesicular transport, prevention of protein aggregation in the cytosol, and cell signaling. They are also linked to autoimmunity, infection immunity, and tumor immunology. Stressors like heat shock, exposure to heavy metals, cytokines, reactive oxygen species, inflammation, and viruses can influence the production of these molecules. In complex diseases such as cancer, malaria, and COVID-19, heat shock proteins are considered both biomarkers and drug targets. The upregulation of small heat shock proteins like hsp27 and major heat shock proteins 70/90 has been recognized as crucial biomarkers and therapeutic targets for cancer. Additionally, it has been reported that the invasion of Plasmodium falciparum, the causative agent of malaria, leads to the upregulation of heat shock proteins such as hsp40, hsp70, and hsp90. This sudden increase is a protective mechanism from the human host and enhances the parasite's growth, making these proteins significant as biomarkers and malarial drug targets. The presence of the SARS-CoV-2 virus in the human cellular system correlates with a substantial increase in heat shock protein 70 production from host cells. Furthermore, our research group has demonstrated that SARS-CoV-2 hijacks the host's heat shock proteins, and we are currently developing tools to prevent the virus from utilizing the host's protein folding system. This review aims to highlight the role of heat shock proteins as biomarkers and therapeutic targets for selected refractory diseases, focusing on cancer, malaria, and COVID-19. A fundamental molecular docking study was performed to investigate the interaction between a non-structural complex from SARS-CoV-2 and chosen small molecules, which is emphasized in this review.

A microaerobically induced small heat shock protein contributes to Rhizobium leguminosarum/Pisum sativum symbiosis and interacts with a wide range of bacteroid proteins.

During the establishment of the symbiosis with legume plants, rhizobia are exposed to hostile physical and chemical microenvironments to which adaptations are required. Stress response proteins including small heat shock proteins (sHSPs) were previously shown to be differentially regulated in bacteroids induced by Rhizobium leguminosarum bv. viciae UPM791 in different hosts. In this work, we undertook a functional analysis of the host-dependent sHSP RLV_1399. A rlv_1399-deleted mutant strain was impaired in the symbiotic performance with peas but not with lentil plants. Expression of rlv_1399 gene was induced under microaerobic conditions in a FnrN-dependent manner consistent with the presence of an anaerobox in its regulatory region. Overexpression of this sHSP improves the viability of bacterial cultures following exposure to hydrogen peroxide and to cationic nodule-specific cysteine-rich (NCR) antimicrobial peptides. Co-purification experiments have identified proteins related to nitrogenase synthesis, stress response, carbon and nitrogen metabolism, and to other relevant cellular functions as potential substrates for RLV_1399 in pea bacteroids. These results, along with the presence of unusually high number of copies of shsp genes in rhizobial genomes, indicate that sHSPs might play a relevant role in the adaptation of the bacteria against stress conditions inside their host.IMPORTANCEThe identification and analysis of the mechanisms involved in host-dependent bacterial stress response is important to develop optimal Rhizobium/legume combinations to maximize nitrogen fixation for inoculant development and might have also applications to extend nitrogen fixation to other crops. The data presented in this work indicate that sHSP RLV_1399 is part of the bacterial stress response to face specific stress conditions offered by each legume host. The identification of a wide diversity of sHSP potential targets reveals the potential of this protein to protect essential bacteroid functions. The finding that nitrogenase is the most abundant RLV_1399 substrate suggests that this protein is required to obtain an optimal nitrogen-fixing symbiosis.

Characterization and functional analysis of small heat shock protein gene HSP20.1 in Bombyx mandarina

Characterization and functional analysis of small heat shock protein gene HSP20.1 in Bombyx mandarina