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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(6): 621-624, 2022 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-35773767

RESUMO

OBJECTIVE: To explore phenotypic and mutational characteristics of a pedigree with distal hereditary motor neuropathy (dHMN). METHODS: Clinical data of the proband and her family members was collected. Electrophysiology, muscle biopsy and whole exome sequencing were carried out for the proband. RESULTS: Patients of the family mainly presented with distal lower limb weakness. Electrophysiological test of the proband revealed distal motor neuropathy and sensory nerves were normal. Muscle biopsy suggested neurogenic atrophy of muscle fibers. Genetic analysis revealed a heterozygous c.421A>G (p.K141E) mutation in exon 2 of the HSPB8 gene, which was a hot spot mutation. CONCLUSION: This family was the first reported HSPB8 related dHMN2A in Chinese population, and p.K141E was the causative mutation, which enriched the mutational spectrum of dHMN in China.


Assuntos
Doença de Charcot-Marie-Tooth , Proteínas de Choque Térmico , Neuropatia Hereditária Motora e Sensorial , Chaperonas Moleculares , Atrofia Muscular Espinal , Doença de Charcot-Marie-Tooth/genética , Feminino , Proteínas de Choque Térmico/genética , Neuropatia Hereditária Motora e Sensorial/genética , Humanos , Chaperonas Moleculares/genética , Atrofia Muscular Espinal/genética , Mutação , Linhagem
2.
Cell Mol Biol (Noisy-le-grand) ; 67(5): 38-44, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35818274

RESUMO

Tuberculosis is a highly contagious infectious disease. Mycobacterium tuberculosis infection is the main cause of tuberculosis. During the infection of M. tuberculosis, the expression of the resistance gene BAG2 will change, and miR-27b will play a certain role in dynamic regulation. The purpose of this article is to explore in-depth the effect of BAG2 on cell autophagy during M. tuberculosis infection and the dynamic regulatory mechanism of miR-27b on BAG2 activated cell autophagy. Fifty rats were used as experimental subjects, and M. tuberculosis strains H37Ra and H37Rv were implanted into the rats. Fluorescence quantitative PCR was used to detect the dynamic changes of BAG2 and miR-27b expression levels in rats and the regulatory effect of miR-27b on BAG2, and the effect of changes in BAG2 expression levels on cell autophagy was studied by immunoblotting. The results showed that after M. tuberculosis-infected macrophages, the expression level of BAG2 decreased from (284.24±6.31) to (156.48.24±4.49), and the expression level of miR-27b was increased from (43.72±3.35) to (78.35± 4.17), the apoptosis rate increased by 17.8%, and the autophagy rate increased by 20.6%. Therefore, it can be seen that the up-regulation of miR-27b expression level during M. tuberculosis infection will inhibit BAG2 expression, thereby promoting cell autophagy and apoptosis to reduce the survival rate of M. tuberculosis.


Assuntos
Autofagia , MicroRNAs , Chaperonas Moleculares , Tuberculose , Animais , Macrófagos/metabolismo , MicroRNAs/genética , Chaperonas Moleculares/metabolismo , Mycobacterium tuberculosis , Ratos , Tuberculose/genética
3.
Front Immunol ; 13: 879657, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35795669

RESUMO

Purpose: The specific mechanisms and biomarkersunderlying the progression of stable coronary artery disease (CAD) to acute myocardial infarction (AMI) remain unclear. The current study aims to explore novel gene biomarkers associated with CAD progression by analyzing the transcriptomic sequencing data of peripheral blood monocytes in different stages of CAD. Material and Methods: A total of 24 age- and sex- matched patients at different CAD stages who received coronary angiography were enrolled, which included 8 patients with normal coronary angiography, 8 patients with angiographic intermediate lesion, and 8 patients with AMI. The RNA from peripheral blood monocytes was extracted and transcriptome sequenced to analyze the gene expression and the differentially expressed genes (DEG). A Gene Oncology (GO) enrichment analysis was performed to analyze the biological function of genes. Weighted gene correlation network analysis (WGCNA) was performed to classify genes into several gene modules with similar expression profiles, and correlation analysis was carried out to explore the association of each gene module with a clinical trait. The dynamic network biomarker (DNB) algorithm was used to calculate the key genes that promote disease progression. Finally, the overlapping genes between different analytic methods were explored. Results: WGCNA analysis identified a total of nine gene modules, of which two modules have the highest positive association with CAD stages. GO enrichment analysis indicated that the biological function of genes in these two gene modules was closely related to inflammatory response, which included T-cell activation, cell response to inflammatory stimuli, lymphocyte activation, cytokine production, and the apoptotic signaling pathway. DNB analysis identified a total of 103 genes that may play key roles in the progression of atherosclerosis plaque. The overlapping genes between DEG/WGCAN and DNB analysis identified the following 13 genes that may play key roles in the progression of atherosclerosis disease: SGPP2, DAZAP2, INSIG1, CD82, OLR1, ARL6IP1, LIMS1, CCL5, CDK7, HBP1, PLAU, SELENOS, and DNAJB6. Conclusions: The current study identified a total of 13 genes that may play key roles in the progression of atherosclerotic plaque and provides new insights for early warning biomarkers and underlying mechanisms underlying the progression of CAD.


Assuntos
Aterosclerose , Doença da Artéria Coronariana , Infarto do Miocárdio , Algoritmos , Doença da Artéria Coronariana/genética , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Proteínas de Choque Térmico HSP40/genética , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Chaperonas Moleculares/genética , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Proteínas do Tecido Nervoso/genética , Proteínas Repressoras/genética
4.
Sci Adv ; 8(30): eabo0517, 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35895815

RESUMO

Nucleosome assembly requires the coordinated deposition of histone complexes H3-H4 and H2A-H2B to form a histone octamer on DNA. In the current paradigm, specific histone chaperones guide the deposition of first H3-H4 and then H2A-H2B. Here, we show that the acidic domain of DNA repair factor APLF (APLFAD) can assemble the histone octamer in a single step and deposit it on DNA to form nucleosomes. The crystal structure of the APLFAD-histone octamer complex shows that APLFAD tethers the histones in their nucleosomal conformation. Mutations of key aromatic anchor residues in APLFAD affect chaperone activity in vitro and in cells. Together, we propose that chaperoning of the histone octamer is a mechanism for histone chaperone function at sites where chromatin is temporarily disrupted.


Assuntos
Histonas , Nucleossomos , DNA/química , Reparo do DNA , Chaperonas de Histonas/genética , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Chaperonas Moleculares/genética
5.
Cell Rep ; 40(3): 111096, 2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858568

RESUMO

Accurate and efficient folding of nascent protein sequences into their native states requires support from the protein homeostasis network. Herein we probe which newly translated proteins are thermo-sensitive, making them susceptible to misfolding and aggregation under heat stress using pulse-SILAC mass spectrometry. We find a distinct group of proteins that is highly sensitive to this perturbation when newly synthesized but not once matured. These proteins are abundant and highly structured. Notably, they display a tendency to form ß sheet secondary structures, have more complex folding topology, and are enriched for chaperone-binding motifs, suggesting a higher demand for chaperone-assisted folding. These polypeptides are also more often components of stable protein complexes in comparison with other proteins. Combining these findings suggests the existence of a specific subset of proteins in the cell that is particularly vulnerable to misfolding and aggregation following synthesis before reaching the native state.


Assuntos
Dobramento de Proteína , Proteoma , Chaperonas Moleculares/metabolismo , Peptídeos/metabolismo , Ligação Proteica , Proteoma/metabolismo
6.
Nat Commun ; 13(1): 4126, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840586

RESUMO

ATP-independent chaperones like trigger factor are generally assumed to play passive roles in protein folding by acting as holding chaperones. Here we show that trigger factor plays a more active role. Consistent with a role as an aggregation inhibiting chaperone, we find that trigger factor rapidly binds to partially folded glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and prevents it from non-productive self-association by shielding oligomeric interfaces. In the traditional view of holding chaperone action, trigger factor would then be expected to transfer its client to a chaperone foldase system for complete folding. Unexpectedly, we noticed that GAPDH folds into a monomeric but otherwise rather native-like intermediate state while trigger factor-bound. Upon release from trigger factor, the mostly folded monomeric GAPDH rapidly self-associates into its native tetramer and acquires enzymatic activity without needing additional folding factors. The mechanism we propose here for trigger factor bridges the holding and folding activities of chaperone function.


Assuntos
Proteínas de Escherichia coli , Proteínas de Escherichia coli/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Dobramento de Proteína
7.
Cell Rep ; 40(2): 111039, 2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35830801

RESUMO

Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1, and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.


Assuntos
Proteínas de Choque Térmico HSP90 , Chaperonas Moleculares , Proteínas de Choque Térmico HSP90/metabolismo , Hormônios/metabolismo , Humanos , Ligantes , Chaperonas Moleculares/metabolismo , Ligação Proteica , Esteroides/metabolismo
8.
Int J Biochem Cell Biol ; 149: 106258, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35777599

RESUMO

Limited treatment options and research in understanding the pathomechanisms of rare diseases has raised concerns about their therapeutic development. One such poorly understood ultra-rare neuromuscular disorder is GNE Myopathy (GNEM) which is caused due to mutation in key sialic acid biosynthetic enzyme, GNE. Treatment with sialic acid or its derivatives/precursors slows the disease progression, but curative strategies need to be explored further. Pathologically, muscle biopsy samples of GNEM patients reveal rimmed vacuole formation due to aggregation of ß-amyloid, Tau, presenilin proteins with unknown mechanism. The present study aims to understand the mechanism of protein aggregate formation in GNE mutant cells to decipher role of chaperones in disease phenotype. The pathologically relevant GNE mutations expressed as recombinant proteins in HEK cells was used as a model system for GNEM to estimate extent of protein aggregation. We identified HSP70, a chaperone, as binding partner of GNE. Downregulation of HSP70 with altered BAG3, JNK, BAX expression levels was observed in GNE mutant cells. The cell apoptosis was observed in GNE mutation specific manner. An activator of HSP70 chaperone, BGP-15, rescued the phenotypic defects due to GNE mutation, thereby, reducing protein aggregation significantly. The results were further validated in rat skeletal muscle cell lines carrying single Gne allele. Our study suggests that HSP70 activators can be a promising therapeutic target in the treatment of ultra-rare GNE Myopathy disease.


Assuntos
Miopatias Distais , Agregados Proteicos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/genética , Miopatias Distais/genética , Miopatias Distais/metabolismo , Miopatias Distais/patologia , Humanos , Chaperonas Moleculares/metabolismo , Músculo Esquelético/metabolismo , Mutação , Ácido N-Acetilneuramínico/metabolismo , Fenótipo
9.
Gene ; 838: 146701, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-35777713

RESUMO

BACKGROUND: Serous ovarian cancer (SOC) is the most common type of ovarian cancer (OC), with bad outcomes. To improve the prognosis of SOC patients, a novel risk signature was developed by combining immunity- and ferroptosis-related genes. METHODS: By means of comparing SOC tissues with normal tissues, we screened the differential expression of immunity-related genes (DE-IRGs) and ferroptosis-related genes(DE-FRGs) with the standards of |log2fold change| > 1 and false discovery rate (FDR) < 0.05. After obtaining the meaningful differentially expressed genes from immune and ferroptosis (DEGs), we established a prognostic risk signature by utilizing Cox regression analyses in TCGA training set, which was validated in TCGA testing set and GSE26712 dataset. Besides, the differential expression of immune-related markers, immunophenoscore (IPS), TIDE score,T cell dysfunction score and T cell exclusion score were also analyzed. We further verified the expression of target genes in ovarian tumor cells lines by QRT-PCR. RESULTS: A risk signature constructed by totally four immunity- and ferroptosis-related DEGs (CXCL11, CX3CR1, FH, and DNAJB6) was developed, which distinguished the SOC patients as high-risk and low-risk groups. Patients in the high-risk group showed a lower overall survival (OS) than those in the low-risk group. Furthermore, the risk score was independent when analyzed with clinical augments, which was significantly associated with 13 KEGG signaling pathways. The gene signature showed favorable predictive performance according to Receiver operating characteristic (ROC) curves. Notably, the expression of immune-related markers or IPS indicated a negative connection with the risk score. SOC patients had a lower score of TIDE and T cell dysfunction than Whom had a higher score. Nonetheless, there were no significant differences in T cell exclusion scores between the two groups.Compared with normal ovarian cell line IOSE-80,QRT-PCR experiments exhibited that CXCL11, CX3CR1and FH were up-regulated in ovarian tumor cells lines(SK-OV-3,COC1,A2780),while DNAJB6 was down-regulated. CONCLUSION: Four-biomarker signature formed by immunity- and ferroptosis-related genes may be clinically used as risk stratifcation tool in serous ovarian cancer,which can help further clinical decision-making regarding prognostic prediction,individualized treatment and follow-up scheduling.


Assuntos
Cistadenocarcinoma Seroso , Ferroptose , Neoplasias Ovarianas , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/genética , Feminino , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP40/genética , Humanos , Chaperonas Moleculares/genética , Proteínas do Tecido Nervoso/genética , Neoplasias Ovarianas/patologia
10.
Life Sci ; 305: 120786, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35809664

RESUMO

AIM: Urinary glycoproteins such as Tamm Horsfall Protein (THP) and Osteopontin (OPN) are well established key regulators of renal stone formation. Additionally, recent revelations have highlighted the influence of Endoplasmic Reticulum (ER) and mitochondria of crucial importance in nephrolithiasis. However, till date conclusive approach highlighting the influence of ER stress on urinary glycoproteins and chaperone in nephrolithiasis remains elusive. Therefore, the present study was focussed on deciphering the possible effect of 4-PBA mitigating ER stress on urinary glycoproteins and calnexin (chaperone) with emphasis on interlinking calcium homeostasis in hyperoxaluric rats. MATERIAL AND METHODS: Post 9 days of treatment, animals were sacrificed, and renal tissues were investigated for urinary glycoproteins, calnexin, calcium homeostasis, ER environment, redox status, and mitochondrial linkage. KEY FINDINGS: 4-PBA appreciably reversed the altered levels of THP, OPN, and calnexin observed along with curtailing the disrupted calcium homeostasis when assessed for SERCA activity and intra-cellular calcium levels. Additionally, significant improvement in the perturbed ER environment as verified by escalated ER stress markers, disturbed protein folding-aggregation-degradation (congo red assay) pathway, and redox status was found post 4-PBA intervention. Interestingly, linkage of ER stress and mitochondria was established under hyperoxaluric conditions when assessed for protein levels of VDAC1 and GRP75. SIGNIFICANCE: 4-PBA treatment resulted in rectifying the repercussions of ER-mitochondrial caused distress when assessed for protein folding/aggregation/degradation events along with disturbed calcium homeostasis. The present study advocates the necessity to adopt a holistic vision towards hyperoxaluria with emphasis on glycoproteins and ER environment.


Assuntos
Hiperoxalúria , Cálculos Renais , Animais , Butilaminas , Cálcio/metabolismo , Calnexina/metabolismo , Calnexina/farmacologia , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Glicoproteínas/metabolismo , Homeostase , Cálculos Renais/etiologia , Cálculos Renais/metabolismo , Mitocôndrias/metabolismo , Chaperonas Moleculares/metabolismo , Ratos
11.
Mol Med Rep ; 26(3)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35795988

RESUMO

Acidic nuclear phosphoprotein 32 family member E (ANP32E) is a histone chaperone that removes H2A.Z from chromatin. ANP32E is implicated in numerous cellular processes, including cell proliferation, apoptosis and cell differentiation. Increasing evidence suggests that dysregulation of ANP32E expression is strongly associated with carcinogenesis. However, the relationship between ANP32E in the development of gastric cancer (GC) is unknown. The present study aimed to explore the potential role of ANP32E in the development of GC using gain­of­function, loss­of­function, CCK­8, colony formation, apoptosis, reverse transcription­quantitative PCR, immunoblotting and luciferase reporter assay. The results of the present study demonstrated that ANP32E expression levels were significantly increased in GC tissues. ANP32E knockdown markedly inhibited GC cell proliferation and colony formation and significantly induced GC cell apoptosis, whereas overexpression of ANP32E significantly induced GC cell malignancy. Furthermore, the results demonstrated that there was a positive association between ANP32E and NUF2 component of NDC80 kinetochore complex (NUF2) expression levels. By assessing NUF2 expression levels, it was demonstrated that ANP32E promoted tumor cell proliferation and inhibited cell apoptosis by increasing NUF2 expression levels in GC cell lines. In conclusion, the present study indicated that ANP32E may function as an efficient oncogene, which promotes tumorigenesis of GC cells by inducing NUF2 expression.


Assuntos
Proteínas de Ciclo Celular , Chaperonas Moleculares , Neoplasias Gástricas , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/genética , Histonas/genética , Histonas/metabolismo , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ativação Transcricional , Regulação para Cima
12.
Biomolecules ; 12(7)2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35883436

RESUMO

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone's nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis.


Assuntos
Proteínas de Choque Térmico HSP90 , Mitocôndrias , Glicólise , Proteínas de Choque Térmico HSP90/metabolismo , Homeostase , Mitocôndrias/metabolismo , Chaperonas Moleculares/metabolismo , Fosforilação Oxidativa
13.
Biomolecules ; 12(7)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35883461

RESUMO

The kinome specific co-chaperone, CDC37 (cell division cycle 37), is responsible for delivering BRAF (B-Rapidly Accelerated Fibrosarcoma) to the Hsp90 (heat shock protein 90) complex, where it is then translocated to the RAS (protooncogene product p21) complex at the plasma membrane for RAS mediated dimerization and subsequent activation. We identify a bipartite interaction between CDC37 and BRAF and delimitate the essential structural elements of CDC37 involved in BRAF recognition. We find an extended and conserved CDC37 motif, 20HPNID---SL--W31, responsible for recognizing the C-lobe of BRAF kinase domain, while the c-terminal domain of CDC37 is responsible for the second of the bipartite interaction with BRAF. We show that dimerization of BRAF, independent of nucleotide binding, can act as a potent signal that prevents CDC37 recognition and discuss the implications of mutations in BRAF and the consequences on signaling in a clinical setting, particularly for class 2 BRAF mutations.


Assuntos
Chaperoninas , Proteínas Proto-Oncogênicas B-raf , Proteínas de Ciclo Celular/metabolismo , Chaperoninas/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas B-raf/genética
14.
Biomolecules ; 12(7)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35883467

RESUMO

"Extracellular" Heat Shock Protein-90 (Hsp90) was initially reported in the 1970s but was not formally recognized until 2008 at the 4th International Conference on The Hsp90 Chaperone Machine (Monastery Seeon, Germany). Studies presented under the topic of "extracellular Hsp90 (eHsp90)" at the conference provided direct evidence for eHsp90's involvement in cancer invasion and skin wound healing. Over the past 15 years, studies have focused on the secretion, action, biological function, therapeutic targeting, preclinical evaluations, and clinical utility of eHsp90 using wound healing, tissue fibrosis, and tumour models both in vitro and in vivo. eHsp90 has emerged as a critical stress-responding molecule targeting each of the pathophysiological conditions. Despite the studies, our current understanding of several fundamental questions remains little beyond speculation. Does eHsp90 indeed originate from purposeful live cell secretion or rather from accidental dead cell leakage? Why did evolution create an intracellular chaperone that also functions as a secreted factor with reported extracellular duties that might be (easily) fulfilled by conventional secreted molecules? Is eHsp90 a safer and more optimal drug target than intracellular Hsp90 chaperone? In this review, we summarize how much we have learned about eHsp90, provide our conceptual views of the findings, and make recommendations on the future studies of eHsp90 for clinical relevance.


Assuntos
Proteínas de Choque Térmico HSP90 , Neoplasias , Movimento Celular , Alemanha , Humanos , Chaperonas Moleculares
15.
Biomolecules ; 12(7)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35883484

RESUMO

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases.


Assuntos
Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Esclerose Tuberosa , Proteínas Supressoras de Tumor , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Chaperonas Moleculares , Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
16.
Proc Natl Acad Sci U S A ; 119(30): e2207414119, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35857868

RESUMO

The Arl4 small GTPases participate in a variety of cellular events, including cytoskeleton remodeling, vesicle trafficking, cell migration, and neuronal development. Whereas small GTPases are typically regulated by their GTPase cycle, Arl4 proteins have been found to act independent of this canonical regulatory mechanism. Here, we show that Arl4A and Arl4D (Arl4A/D) are unstable due to proteasomal degradation, but stimulation of cells by fibronectin (FN) inhibits this degradation to promote Arl4A/D stability. Proteomic analysis reveals that FN stimulation induces phosphorylation at S143 of Arl4A and at S144 of Arl4D. We identify Pak1 as the responsible kinase for these phosphorylations. Moreover, these phosphorylations promote the chaperone protein HYPK to bind Arl4A/D, which stabilizes their recruitment to the plasma membrane to promote cell migration. These findings not only advance a major mechanistic understanding of how Arl4 proteins act in cell migration but also achieve a fundamental understanding of how these small GTPases are modulated by revealing that protein stability, rather than the GTPase cycle, acts as a key regulatory mechanism.


Assuntos
Fatores de Ribosilação do ADP , Proteínas de Transporte , Membrana Celular , Chaperonas Moleculares , Fatores de Ribosilação do ADP/metabolismo , Proteínas de Transporte/metabolismo , Membrana Celular/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Fosforilação , Ligação Proteica , Proteômica
17.
PLoS One ; 17(7): e0257786, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35895711

RESUMO

Mislocalised membrane proteins (MLPs) present a risk to the cell due to exposed hydrophobic amino acids which cause MLPs to aggregate. Previous studies identified SGTA as a key component of the machinery that regulates the quality control of MLPs. Overexpression of SGTA promotes deubiqutination of MLPs resulting in their accumulation in cytosolic inclusions, suggesting SGTA acts in collaboration with deubiquitinating enzymes (DUBs) to exert these effects. However, the DUBs that play a role in this process have not been identified. In this study we have identified the ubiquitin specific peptidase 5 (USP5) as a DUB important in regulating the quality control of MLPs. We show that USP5 is in complex with SGTA, and this association is increased in the presence of an MLP. Overexpression of SGTA results in an increase in steady-state levels of MLPs suggesting a delay in proteasomal degradation of substrates. However, our results show that this effect is strongly dependent on the presence of USP5. We find that in the absence of USP5, the ability of SGTA to increase the steady state levels of MLPs is compromised. Moreover, knockdown of USP5 results in a reduction in the steady state levels of MLPs, while overexpression of USP5 increases the steady state levels. Our findings suggest that the interaction of SGTA with USP5 enables specific MLPs to escape proteasomal degradation allowing selective modulation of MLP quality control. These findings progress our understanding of aggregate formation, a hallmark in a range of neurodegenerative diseases and type II diabetes, as well as physiological processes of aggregate clearance.


Assuntos
Endopeptidases , Chaperonas Moleculares , Citosol/metabolismo , Endopeptidases/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/metabolismo
18.
Indian J Pathol Microbiol ; 65(3): 598-603, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35900487

RESUMO

Objective: Cancer cells activate either telomerase or alternative lengthening of telomeres (ALT) to maintain telomere length and achieve immortalization. Alpha thalassemia/mental retardation X-linked (ATRX) is involved in chromatin remodeling. Mutations in ATRX genes are associated with the loss of nuclear expression and correlated with the ALT phenotype. ATRX expression has been evaluated in various cancers, especially sarcoma and neuroendocrine tumors, and its clinical significance has been shown to be diverse, depending on the tumor types. The role and prognostic value of ATRX expression in clear cell renal cell carcinoma (CCRCC) have not been elucidated. Methods: We investigated the messenger RNA (mRNA) expression levels of ATRX using the gene expression profiling interactive analysis (GEPIA) database and evaluated the expression of ATRX using immunohistochemical (IHC) staining in 302 CCRCC cases. Results: Loss of ATRX expression was significantly associated with larger tumor size, higher nuclear grade (NG), lymphovascular invasion (LVI), pathologic T (pT) stage, recurrence/metastasis, and stage. Although ATRX was not an independent prognostic factor, patients with loss of ATRX expression showed poor survival. Conclusion: Our findings suggest that loss of ATRX expression could be a potential biomarker for predicting aggressive tumor behavior and poor clinical outcomes in CCRCC.


Assuntos
Carcinoma de Células Renais , Deficiência Intelectual , Neoplasias Renais , Talassemia alfa , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Proteínas Correpressoras , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Chaperonas Moleculares/genética , Proteínas Nucleares/análise , Proteínas Nucleares/genética , Prognóstico , Homeostase do Telômero , Proteína Nuclear Ligada ao X/genética
19.
Molecules ; 27(14)2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35889400

RESUMO

The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (α7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance to Inhibitors of Cholinesterase 3 (RIC-3) and Nicotinic Acetylcholine Receptor Regulator (NACHO). Recent cryo-EM and NMR data revealed structural features of α7 nAChRs. A ser-ala-pro (SAP) motif precedes a structurally important but unique "latch" helix in α7 nAChRs. A sampling of α7 sequences suggests the SAP motif is conserved from C. elegans to humans, but the latch sequence is only conserved in vertebrates. How RIC-3 and NACHO facilitate receptor subunits folding into their final pentameric configuration is not known. The artificial intelligence program AlphaFold2 recently predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. This review ponders how different intrinsically disordered RIC-3 isoforms from C. elegans to humans interact with α7 nAChR subunits despite having little sequence homology across RIC-3 species. Two models from the literature about how RIC-3 assists α7 nAChR assembly are evaluated considering recent structural information about the receptor and its chaperones.


Assuntos
Receptores Nicotínicos , Animais , Inteligência Artificial , Caenorhabditis elegans/metabolismo , Colinesterases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Chaperonas Moleculares/metabolismo , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/genética , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
20.
Biomolecules ; 12(8)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35892339

RESUMO

The folding of the myosin head often requires a UCS (Unc45, Cro1, She4) domain-containing chaperone. Worms, flies, and fungi have just a single UCS protein. Vertebrates have two; one (Unc45A) which functions primarily in non-muscle cells and another (Unc45B) that is essential for establishing and maintaining the contractile apparatus of cardiac and skeletal muscles. The domain structure of these proteins suggests that the UCS function evolved before animals and fungi diverged from a common ancestor more than a billion years ago. UCS proteins of metazoans and apicomplexan parasites possess a tetratricopeptide repeat (TPR), a domain for direct binding of the Hsp70/Hsp90 chaperones. This, however, is absent in the UCS proteins of fungi and largely nonessential for the UCS protein function in Caenorhabditis elegans and zebrafish. The latter part of this review focusses on the TPR-deficient UCS proteins of fungi. While these are reasonably well studied in yeasts, there is little precise information as to how they might engage in interactions with the Hsp70/Hsp90 chaperones or might assist in myosin operations during the hyphal growth of filamentous fungi.


Assuntos
Chaperonas Moleculares , Peixe-Zebra , Animais , Caenorhabditis elegans/metabolismo , Fungos/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Chaperonas Moleculares/metabolismo , Miosinas/metabolismo , Ligação Proteica , Peixe-Zebra/metabolismo
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