Heat Shock Transcription Factor Research Articles

The in vivo performance of a heat shock transcription factor from Populus euphratica, PeHSFA2, promises a prospective strategy to alleviate heat stress damage in poplar

Heat stress driven by global warming has affected forest yields and survival at a larger scale in recent decades, hence breeding heat-tolerant tree species has become imperative. We here investigated the role of PeHSFA2, a crucial gene in plant heat shock response from Populus euphratica, in regulating plant heat stress protection. PeHSFA2 is localized to the cytoplasm and nucleus and can be transported from the cytoplasm into the nucleus under detrimental high-temperature conditions. Poplar plants with overexpressed PeHSFA2 outperformed the control group when subjected to severe heat stress, for they had higher leaf water content, lower leaf relative electrolyte leakage, and better photosynthetic activity after heat treatment. The results of qRT-PCR analyses revealed that PeHSFA2 regulates the transcription of a group of heat-protective genes including small heat shock protein, GALACTINOL SYNTHASE 2.2, and ASCORBATE PEROXIDASE 2 in white poplar. Transactivation assays confirmed that PeHSFA2 activated the expression of PtoHSP19.9, PtoHSP21.3, PtoHSP21.8, PtoHSP22.0, PtoGOLS2.2, and PtoAPX2 via binding to the promoter regions of these genes. These results emphasize the point that PeHSFA2 can vehemently reinforce plant thermotolerance via regulating the transcription of a set of heat shock response genes, and PeHSFA2 possesses enormous potential in breeding poplar plants with substantially enhanced thermotolerance.

A heat shock transcription factor gene (HaHSFA1) from a desert shrub, Haloxylon ammodendron, elevates salt tolerance in Arabidopsis thaliana

Haloxylon ammodendron is a typical desert xerophyte with worthy genetic resources, therefore, it is necessary to explore the resistance genes of H. ammodendron , and to improve the stress tolerance of other plant species through genetic engineering. In this study, a heat shock transcription factor gene, HaHSFA1 , was firstly cloned from H. ammodendron and overexpressed in Arabidopsis thaliana . The sensitivity of transgenic plants to exogenous ABA, osmotic stress and salt stress were analyzed; the effects of overexpression of HaHSFA1 in Arabidopsis on salt tolerance were deeply investigated. The results indicated that overexpression of HaHSFA1 increased chlorophyll content in Arabidopsis, and the growth of plants was promoted. The leaf soluble sugar and proline contents in OE lines were significantly increased compared with those in WT. OE lines maintained lower osmotic potential and higher shoot water content. Overexpression of HaHSFA1 in Arabidopsis also enhanced antioxidant activity, which may be important for protecting plasma membrane integrity in cells. Overexpression of HaHSFA1 in Arabidopsis improved root activity and increased selective absorption and transport capacity for K + over Na + , which was of great significance to reduce the toxic effect of Na + . This study indicated that overexpression of HaHSFA1 from H. ammodendron significantly elevates the salt tolerance of Arabidopsis, and HaHSFA1 has potential application values in improving abiotic stress tolerance in crops by genetic engineering. • HaHSFA1 was firstly cloned from a desert shrub, Haloxylon ammodendron . • Overexpression of HaHSFA1 enhanced osmotic adjustment and ROS scavenging ability in Arabidopsis. • Overexpression of HaHSFA1 maintained higher selectivity of absorption and transport for K + over Na + in Arabidopsis.

Brassinosteroids promote thermotolerance through releasing BIN2-mediated phosphorylation and suppression of HsfA1 transcription factors in Arabidopsis

High temperature adversely affects plant growth and development. The steroid phytohormones brassinosteroids (BRs) are recognized to play important roles in plant heat stress responses and thermotolerance, but the underlying mechanisms remain obscure. Here, we demonstrate that the glycogen synthase kinase 3 (GSK3)-like kinase BRASSINOSTEROID INSENSITIVE2 (BIN2), a negative component in the BR signaling pathway, interacts with the master heat-responsive transcription factors CLASS A1 HEAT SHOCK TRANSCRIPTION FACTORS (HsfA1s). Furthermore, BIN2 phosphorylates HsfA1d on T263 and S56 to suppress its nuclear localization and inhibit its DNA-binding ability, respectively. BR signaling promotes plant thermotolerance by releasing the BIN2 suppression of HsfA1d to facilitate its nuclear localization and DNA binding. Our study provides insights into the molecular mechanisms by which BRs promote plant thermotolerance by strongly regulating HsfA1d through BIN2 and suggests potential ways to improve crop yield under extreme high temperatures.

Biological characteristics of heat shock transcription factors and their roles in abiotic stress adaptation of higher plant

Heat shock transcription factors (HSFs) are involved in the regulation of plant growth and development. Furthermore, HSFs regulate the expression of a series of genes related to various abiotic stress adaptations. HSFs usually form homotrimers to activate their transcriptional activity and function. Here, we review the basic structure, subcellular localization, transcriptional regulation, functional diversity of HSFs, and their roles in plant adaptation to abiotic stresses, such as extreme temperature, salinity, drought, strong light and oxidative stress, etc. HSFs are high-quality candidate genes for improving the resistance of higher plants to multiple stresses. Studies of HSFs have important application value. In the future, using HSFs to improve the resistance of various crops through genetic engineering would be prospects of development.

An 85-amino-acid polypeptide from Myrmeleon bore larvae (antlions) homologous to heat shock factor binding protein 1 with antiproliferative activity against MG-63 osteosarcoma cells in vitro.

Venomous arthropods have substances in their venom with antiproliferative potential for neoplastic cells. To identify a polypeptide from Myrmeleon bore (antlion) with antiproliferative activity against neoplastic cells, and to elucidate the molecular mechanism of the activity. We used gel filtration and ion exchange chromatography to purify a polypeptide with antiproliferative activity against MG-63 human osteosarcoma cells from a proteinaceous extract of antlion. The polypeptide was sequenced and the stability of its antiproliferative activity was tested under a range of conditions in vitro. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the antiproliferative activity of the polypeptide against the MG-63 osteosarcoma cells and MC3T3-E1 mouse calvarial osteoblasts, which were used as a non-neoplastic control. We used western blotting to compare the levels of expression of heat shock transcription factor 1 (HSF1), heat shock protein 90 (HSP90), cyclin-dependent kinase 4 (CDK4), and protein kinase B alpha (ATK1) in MG-63 osteosarcoma cells and their mouse homologs in MC3T3-E1 osteoblasts after their treatment with the antlion antiproliferative polypeptide (ALAPP). The 85-amino-acid ALAPP has a 56% sequence identity with the human heat shock factor binding protein 1 (HSBP1). The antiproliferative activity of the polypeptide is relatively insensitive to temperature, pH, and metal ions. ALAPP has a strong concentration-dependent antiproliferative activity against MG-63 osteosarcoma cells compared with its effect on MC3T3-E1 osteoblasts. ALAPP significantly upregulates the expression of HSF1 in MC3T3-EL osteoblasts, but not in MG-63 osteosarcoma. ALAPP significantly downregulated the expression of HSP90, CDK4, and AKT1 expression in MG-63 osteosarcoma, but not in the osteoblasts. ALAPP has significant antiproliferative activity against MG-63 osteosarcoma cells, but not nonneoplastic MC3T3-E1 osteoblasts. We speculate that non-neoplastic cells may evade the antiproliferative effect of ALAPP by upregulating HSF1 to maintain their HSP90, CDK4, and AKT1 expression at a relatively constant level.

Beat the heat: plant- and microbe-mediated strategies for crop thermotolerance.

Heat stress (HS) affects plant growth and development, and reduces crop yield. To combat HS, plants have evolved several sophisticated strategies. The primary HS response in plants involves the activation of heat-shock transcription factors and heat-shock proteins (HSPs). Plants also deploy more advanced epigenetic mechanisms in response to recurring HS conditions. In addition, beneficial microbes can reprogram the plant epitranscriptome to induce thermotolerance, and have the potential to improve crop yield productivity by mitigating HS-induced inhibition of growth and development. We summarize the latest advances in plant epigenetic regulation and highlight microbe-mediated thermotolerance in plants.

HSF1 phosphorylation establishes an active chromatin state via the TRRAP–TIP60 complex and promotes tumorigenesis

Transcriptional regulation by RNA polymerase II is associated with changes in chromatin structure. Activated and promoter-bound heat shock transcription factor 1 (HSF1) recruits transcriptional co-activators, including histone-modifying enzymes; however, the mechanisms underlying chromatin opening remain unclear. Here, we demonstrate that HSF1 recruits the TRRAP-TIP60 acetyltransferase complex in HSP72 promoter during heat shock in a manner dependent on phosphorylation of HSF1-S419. TRIM33, a bromodomain-containing ubiquitin ligase, is then recruited to the promoter by interactions with HSF1 and a TIP60-mediated acetylation mark, and cooperates with the related factor TRIM24 for mono-ubiquitination of histone H2B on K120. These changes in histone modifications are triggered by phosphorylation of HSF1-S419 via PLK1, and stabilize the HSF1-transcription complex in HSP72 promoter. Furthermore, HSF1-S419 phosphorylation is constitutively enhanced in and promotes proliferation of melanoma cells. Our results provide mechanisms for HSF1 phosphorylation-dependent establishment of an active chromatin status, which is important for tumorigenesis.

The Karrikin Receptor Karrikin Insensitive2 Positively Regulates Heat Stress Tolerance in Arabidopsis thaliana.

In this study, we investigated the potential role of the karrikin receptor KARRIKIN INSENSITIVE2 (KAI2) in the response of Arabidopsis seedlings to high-temperature stress. We performed phenotypic, physiological and transcriptome analyses of Arabidopsis kai2 mutants and wild-type (WT) plants under control (kai2_C and WT_C, respectively) and 6- and 24-h heat stress conditions (kai2_H6, kai2_H24, WT_H6 and WT_H24, respectively) to understand the basis for KAI2-regulated heat stress tolerance. We discovered that the kai2 mutants exhibited hypersensitivity to high-temperature stress relative to WT plants, which might be associated with a more highly increased leaf surface temperature and cell membrane damage in kai2 mutant plants. Next, we performed comparative transcriptome analysis of kai2_C, kai2_H6, kai2_H24, WT_C, WT_H6 and WT_H24 to identify transcriptome differences between WT and kai2 mutants in response to heat stress. K-mean clustering of normalized gene expression separated the investigated genotypes into three clusters based on heat-treated and non-treated control conditions. Within each cluster, the kai2 mutants were separated from WT plants, implying that kai2 mutants exhibited distinct transcriptome profiles relative to WT plants. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed a repression in 'misfolded protein binding', 'heat shock protein binding', 'unfolded protein binding' and 'protein processing in endoplasmic reticulum' pathways, which was consistent with the downregulation of several genes encoding heat shock proteins and heat shock transcription factors in the kai2 mutant versus WT plants under control and heat stress conditions. Our findings suggest that chemical or genetic manipulation of KAI2 signaling may provide a novel way to improve heat tolerance in plants.

Genome-Wide Identification of Eucalyptus Heat Shock Transcription Factor Family and Their Transcriptional Analysis under Salt and Temperature Stresses.

Heat shock transcription factors (HSFs) activate heat shock protein gene expression by binding their promoters in response to heat stress and are considered to be pivotal transcription factors in plants. Eucalyptus is a superior source of fuel and commercial wood. During its growth, high temperature or other abiotic stresses could impact its defense capability and growth. Hsf genes have been cloned and sequenced in many plants, but rarely in Eucalyptus. In this study, we used bioinformatics methods to analyze and identify Eucalyptus Hsf genes, their chromosomal localization and structure. The phylogenetic relationship and conserved domains of their encoded proteins were further analyzed. A total of 36 Hsf genes were identified and authenticated from Eucalyptus, which were scattered across 11 chromosomes. They could be classified into three classes (A, B and C). Additionally, a large number of stress-related cis-regulatory elements were identified in the upstream promoter sequence of HSF, and cis-acting element analysis indicated that the expression of EgHsf may be regulated by plant growth and development, metabolism, hormones and stress responses. The expression profiles of five representative Hsf genes, EgHsf4, EgHsf9, EgHsf13, EgHsf24 and EgHsf32, under salt and temperature stresses were examined by qRT-PCR. The results show that the expression pattern of class B genes (EgHsf4, EgHsf24 and EgHsf32) was more tolerant to abiotic stresses than that of class A genes (EgHsf9 and EgHsf13). However, the expressions of all tested Hsf genes in six tissues were at different levels. Finally, we investigated the network of interplay between genes, and the results suggest that there may be synergistic effects between different Hsf genes in response to abiotic stresses. We conclude that the Hsf gene family played an important role in the growth and developmental processes of Eucalyptus and could be vital for maintaining cell homeostasis against external stresses. This study provides basic information on the members of the Hsf gene family in Eucalyptus and lays the foundation for the functional identification of related genes and the further investigation of their biological functions in plant stress regulation.

Diversification of heat shock transcription factors expanded thermal stress responses during early plant evolution.

The copy numbers of many plant transcription factor (TF) genes substantially increased during terrestrialization. This allowed TFs to acquire new specificities and thus create gene regulatory networks (GRNs) with new biological functions to help plants adapt to terrestrial environments. Through characterizing heat shock factor (HSF) genes MpHSFA1 and MpHSFB1 in the liverwort Marchantia polymorpha, we explored how heat-responsive GRNs widened their functions in M. polymorpha and Arabidopsis thaliana. An interspecies comparison of heat-induced transcriptomes and the evolutionary rates of HSFs demonstrated the emergence and subsequent rapid evolution of HSFB prior to terrestrialization. Transcriptome and metabolome analyses of M. polymorpha HSF-null mutants revealed that MpHSFA1 controls canonical heat responses such as thermotolerance and metabolic changes. MpHSFB1 also plays essential roles in heat responses, as well as regulating developmental processes including meristem branching and antheridiophore formation. Analysis of cis-regulatory elements revealed development- and stress-related TFs that function directly or indirectly downstream of HSFB. Male gametophytes of M. polymorpha showed higher levels of thermotolerance than female gametophytes, which could be explained by different expression levels of MpHSFA1U and MpHSFA1V on sex chromosome. We propose that the diversification of HSFs is linked to the expansion of HS responses, which enabled coordinated multicellular reactions in land plants.

DELAYED HEADING DATE3, Encoding a Heat Shock Transcription Factor, Delays Flowering Time and Improves Yield in Rice (Oryza sativa L.)

Heading date is an essential agronomic trait that affects adaptability and yield in rice (Oryza sativa). HSFs (heat shock transcription factors) are a type of transcription factor that responds to environmental stress in organisms. The relationship between the heading date and HSFs has been seldom reported so far. Here, we identified a new heat shock transcription factor, named DELAYED HEADING DATE3 (DHD3), which can significantly delay the heading date by about 14 days and provide improvements of about 77% potential yield in rice. DHD3 protein is localized in the nucleus and has weak transactivation activity. DHD3 delays the heading date by significantly suppressing Hd3a and RFT1 expression under long-day (LD) and short-day (SD) conditions. Furthermore, the low-temperature condition greatly enhances the delay effect of DHD3 on the heading date (from 16.1% to more than 89.3%). We propose that DHD3 may involve the temperature-regulated signaling pathway of flowering time in rice and has the potential to improve crop yield.

HSF-1: Guardian of the Proteome Through Integration of Longevity Signals to the Proteostatic Network.

Discoveries made in the nematode Caenorhabditis elegans revealed that aging is under genetic control. Since these transformative initial studies, C. elegans has become a premier model system for aging research. Critically, the genes, pathways, and processes that have fundamental roles in organismal aging are deeply conserved throughout evolution. This conservation has led to a wealth of knowledge regarding both the processes that influence aging and the identification of molecular and cellular hallmarks that play a causative role in the physiological decline of organisms. One key feature of age-associated decline is the failure of mechanisms that maintain proper function of the proteome (proteostasis). Here we highlight components of the proteostatic network that act to maintain the proteome and how this network integrates into major longevity signaling pathways. We focus in depth on the heat shock transcription factor 1 (HSF1), the central regulator of gene expression for proteins that maintain the cytosolic and nuclear proteomes, and a key effector of longevity signals.

Heat Shock Transcription Factor 2 Promotes Mitophagy of Intestinal Epithelial Cells Through PARL/PINK1/Parkin Pathway in Ulcerative Colitis.

The overactivation of NLRP3 inflammasome in intestinal epithelial cells (IECs) is among the important reasons for severe inflammation in ulcerative colitis (UC). We found that heat shock transcription factor 2 (HSF2), which is highly expressed in UC, could inhibit the activation of NLRP3 inflammasome and reduce IL-1β in IECs, but the mechanisms were still not clear. It has been reported that HSP72 regulated by HSF2 can enhance the mitophagy mediated by Parkin. The number of damaged mitochondria and the mitochondrial derived ROS (mtROS) can be reduced by mitophagy, which means the activity of NLRP3 inflammasome is inhibited. Therefore, we speculate that HSF2 might regulate the activation of NLRP3 inflammasome of IECs in UC through the mitophagy mediated by Parkin. This study proves that the number of damaged mitochondria in IECs, the level of mitophagy, and the level of ROS in intestinal mucosa are positively correlated with the severity of UC. In mice and cells, mitophagy was promoted by HSF2 through the PARL/PINK1/Parkin pathway. This study reveals the potential mechanisms of HSF2 decreasing mtROS of IECs in UC.

Elucidation of Heat Shock Transcription Factor Family (HSFs) Postulates Significant Insights for the Identification of Their Putative Roles in Root Development and Hormonal Regulation in Tomato

Elucidation of Heat Shock Transcription Factor Family (HSFs) Postulates Significant Insights for the Identification of Their Putative Roles in Root Development and Hormonal Regulation in Tomato

HEAT SHOCK TRANSCRIPTION FACTOR B2b acts as a transcriptional repressor of VIN3, a gene induced by long-term cold for flowering

Vernalization, an acceleration of flowering after long-term winter cold, is an intensively studied flowering mechanism in winter annual plants. In Arabidopsis, Polycomb Repressive Complex 2 (PRC2)-mediated suppression of the strong floral repressor, FLOWERING LOCUS C (FLC), is critical for vernalization and a PHD finger domain protein, VERNALIZATION INSENSITIVE 3 (VIN3), recruits PRC2 on FLC chromatin. The level of VIN3 was found to gradually increase in proportion to the length of cold period during vernalization. However, how plants finely regulate VIN3 expression according to the cold environment has not been completely elucidated. As a result, we performed EMS mutagenesis using a transgenic line with a minimal promoter of VIN3 fused to the GUS reporter gene, and isolated a mutant, hyperactivation of VIN3 1 (hov1), which showed increased GUS signal and endogenous VIN3 transcript levels. Using positional cloning combined with whole-genome resequencing, we found that hov1 carries a nonsense mutation, leading to a premature stop codon on the HEAT SHOCK TRANSCRIPTION FACTOR B2b (HsfB2b), which encodes a repressive heat shock transcription factor. HsfB2b directly binds to the VIN3 promoter, and HsfB2b overexpression leads to reduced acceleration of flowering after vernalization. Collectively, our findings reveal a novel fine-tuning mechanism to regulate VIN3 for proper vernalization response.

Characteristics and Regulating Roles of Wheat TaHsfA2-13 in Abiotic Stresses.

Heat shock transcription factor (Hsf) exists widely in eukaryotes and responds to various abiotic stresses by regulating the expression of downstream transcription factors, functional enzymes, and molecular chaperones. In this study, TaHsfA2-13, a heat shock transcription factor belonging to A2 subclass, was cloned from wheat (Triticum aestivum) and its function was analyzed. TaHsfA2-13 encodes a protein containing 368 amino acids and has the basic characteristics of Hsfs. Multiple sequence alignment analysis showed that TaHsfA2-13 protein had the highest similarity with TdHsfA2c-like protein from Triticum dicoccoides, which reached 100%. The analysis of tissue expression characteristics revealed that TaHsfA2-13 was highly expressed in root, shoot, and leaf during the seedling stage of wheat. The expression of TaHsfA2-13 could be upregulated by heat stress, low temperature, H2O2, mannitol, salinity and multiple phytohormones. The TaHsfA2-13 protein was located in the nucleus under the normal growth conditions and showed a transcriptional activation activity in yeast. Further studies found that overexpression of TaHsfA2-13 in Arabidopsis thaliana Col-0 or athsfa2 mutant results in improved tolerance to heat stress, H2O2, SA and mannitol by regulating the expression of multiple heat shock protein (Hsp) genes. In summary, our study identified TaHsfA2-13 from wheat, revealed its regulatory function in varieties of abiotic stresses, and will provide a new target gene to improve stress tolerance for wheat breeding.

Genome-wide analysis and characterization of heat shock transcription factors (Hsfs) in common bean (Phaseolus vulgaris L.).

Heat shock transcription factors (Hsfs) play an essential role as transcriptional regulatory proteins against heat stress by controlling the expression of heat-responsive genes. Common bean is a highly thermosensitive crop, and, therefore, its genome sequence information is segregated, characterized here in terms of heat shock transcription factors and its evolutionary significance. In this study, a complete comprehensive set of 29 non-redundant full-length Hsf genes were identified and characterized from Phaseolus vulgaris L. (PvHsf) genome sequence. Detailed gene information such as chromosomal localization, domain position, motif organization, and exon-intron identification were analyzed. All the 29 PvHsf genes were mapped on 8 out of 11 chromosomes, indicating the gene duplication occurred in the common bean genome. Motif analysis and exon-intron structure were conserved in each group, which showed that the cytoplasmic proteins highly influence the conserved structure of PvHsfs and heat-induced response. The HSF genes were grouped into three classes, i.e., A to C and 14 groups, based on structural features and phylogenetic relationships. Only one pair of paralog sequences suggests that it may be derived from the duplication event during evolution. A comparative genomics study indicated the influence of whole-genome duplication and purifying selection on the common bean genome during development. In silico expression analysis showed the active role of class A and B family during abiotic stress conditions and higher expression in floral organs. The qRT-PCR analysis revealed PvHSFA8 as the master regulator and PvHSFB1A and PvHSFB2A induction during heat exposure in French beans.

Heat shock factor HSFA2 fine-tunes resetting of thermomemory via plastidic metalloprotease FtsH6.

Plants 'memorize' stressful events and protect themselves from future, often more severe, stresses. To maximize growth after stress, plants 'reset' or 'forget' memories of stressful situations, which requires an intricate balance between stress memory formation and the degree of forgetfulness. HEAT SHOCK PROTEIN 21 (HSP21) encodes a small heat shock protein in plastids of Arabidopsis thaliana. HSP21 functions as a key component of thermomemory, which requires a sustained elevated level of HSP21 during recovery from heat stress. A heat-induced metalloprotease, filamentation temperature-sensitive H6 (FtsH6), degrades HSP21 to its pre-stress abundance, thereby resetting memory during the recovery phase. The transcription factor heat shock factor A2 (HSFA2) activates downstream genes essential for mounting thermomemory, acting as a positive regulator in the process. Here, using a yeast one-hybrid screen, we identify HSFA2 as an upstream transactivator of the resetting element FtsH6. Constitutive and inducible overexpression of HSFA2 increases expression of FtsH6, whereas it is drastically reduced in the hsfa2 knockout mutant. Chromatin immunoprecipitation reveals in planta binding of HSFA2 to the FtsH6 promoter. Importantly, overexpression of HSFA2 improves thermomemory more profoundly in ftsh6 than wild-type plants. Thus, by activating both memory-supporting and memory-resetting genes, HSFA2 acts as a cellular homeostasis factor during thermomemory.

Praja1 RING-finger E3 ubiquitin ligase is a common suppressor of neurodegenerative disease-associated protein aggregation.

The formation of misfolded protein aggregates is one of the pathological hallmarks of neurodegenerative diseases. We have previously demonstrated the cytoplasmic aggregate formation of adenovirally expressed transactivation response DNA-binding protein of 43 kDa (TDP-43), the main constituent of neuronal cytoplasmic aggregates in cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), in cultured neuronal cells under the condition of proteasome inhibition. The TDP-43 aggregate formation was markedly suppressed by co-infection of adenoviruses expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response, and Praja1 RING-finger E3 ubiquitin ligase (PJA1) located downstream of the HSF1 pathway. In the present study, we examined other reportedly known E3 ubiquitin ligases for TDP-43, i.e. Parkin, RNF112 and RNF220, but failed to find their suppressive effects on neuronal cytoplasmic TDP-43 aggregate formation, although they all bind to TDP-43 as verified by co-immunoprecipitation. In contrast, PJA1 also binds to adenovirally expressed wild-type and mutated fused in sarcoma, superoxide dismutase 1, α-synuclein and ataxin-3, and huntingtin polyglutamine proteins in neuronal cultures and suppressed the aggregate formation of these proteins. These results suggest that PJA1 is a common sensing factor for aggregate-prone proteins to counteract their aggregation propensity, and could be a potential therapeutic target for neurodegenerative diseases that include ALS, FTLD, Parkinson's disease and polyglutamine diseases.

Mitochondrial HSF1 triggers mitochondrial dysfunction and neurodegeneration in Huntington's disease

Aberrant localization of proteins to mitochondria disturbs mitochondrial function and contributes to the pathogenesis of Huntington’s disease (HD). However, the crucial factors and the molecular mechanisms remain elusive. Here, we found that heat shock transcription factor 1 (HSF1) accumulates in the mitochondria of HD cell models, a YAC128 mouse model, and human striatal organoids derived from HD induced pluripotent stem cells (iPSCs). Overexpression of mitochondria‐targeting HSF1 (mtHSF1) in the striatum causes neurodegeneration and HD‐like behavior in mice. Mechanistically, mtHSF1 facilitates mitochondrial fission by activating dynamin‐related protein 1 (Drp1) phosphorylation at S616. Moreover, mtHSF1 suppresses single‐stranded DNA‐binding protein 1 (SSBP1) oligomer formation, which results in mitochondrial DNA (mtDNA) deletion. The suppression of HSF1 mitochondrial localization by DH1, a unique peptide inhibitor, abolishes HSF1‐induced mitochondrial abnormalities and ameliorates deficits in an HD animal model and human striatal organoids. Altogether, our findings describe an unsuspected role of HSF1 in contributing to mitochondrial dysfunction, which may provide a promising therapeutic target for HD.