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Huaqin Wang - One of the best experts on this subject based on the ideXlab platform.
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BAG3-positive pancreatic stellate cells promote migration and invasion of pancreatic ductal adenocarcinoma.
Journal of Cellular and Molecular Medicine, 2019Co-Authors: Ye Yuan, Jiamei Wang, Xiaona Meng, Jing‐yi Jiang, Chao Li, Huaqin WangAbstract:: BAG3 is constitutively expressed in multiple types of cancer cells and its high expression is associated with tumour progression and poor prognosis of PDAC. However, little is known about the role of BAG3 in the regulation of stromal microenvironment of PDAC. The current study demonstrated that beside PDAC tumour cells, BAG3 was also expressed in some activated stroma cells in PDAC tissue, as well as in activated PSCs. In addition, the current study demonstrated that BAG3 expression in PSCs was involved in maintenance of PSCs activation and promotion of PDACs invasion via releasing multiple cytokines. The current study demonstrated that BAG3-positive PSCs promoted invasion of PDACs via IL-8, MCP1, TGF-β2 and IGFBP2 in a paracrine manner. Furthermore, BAG3 sustained PSCs activation through IL-6, TGF-β2 and IGFBP2 in an autocrine manner. Thereby, the current study provides a new insight into the involvement of BAG3 in remodelling of stromal microenvironment favourable for malignant progression of PDAC, indicating that BAG3 might serve as a potential target for anti-fibrosis of PDAC.
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BAG3 Suppresses Loading of Ago2 to IL6 mRNA in Pancreatic Ductal Adenocarcinoma
Frontiers in Oncology, 2019Co-Authors: Chao Li, Mingxin An, Xinyu Li, Si Li, Jingyi Jiang, Huaqin WangAbstract:Pancreatic stellate cells (PSCs) are a subset of pancreatic cancer-associated fibroblasts, which play a critical role in pancreatic fibrosis, a characteristic feature of pancreatic cancer. The interplay between PSCs and pancreatic cancer cells is vital for promotion of tumor progression and metastasis. BAG3 is correlated with poor prognostics in patients with pancreatic ductal adenocarcinoma (PDAC), however, the exact mechanisms remain largely unknown. In this study, we demonstrated that BAG3 downregulation decreased IL6 release by PDACs, and IL6 reduction was, at least partially, responsible for suppression of PSCs activation by PDACs with BAG3 downmodulation. Importantly, BAG3 expression positively correlated with fibrosis in pancreatic cancer tissue. With regard to the underlying mechanism, we demonstrated that BAG3 knockdown facilitated recruitment of Agonaute 2 (Ago2) to IL6 mRNA, resulting in destabilization of IL6 mRNA. In addition, the current study demonstrated that phosphorylation at Serine (Ser) 387 site was required for recruitment of Ago2-containing miRISC to IL6 mRNA and BAG3 knockdown facilitated Ago2 loading to IL6 mRNA via increasing its phosphorylation at Ser 387. This study shed new light on the tumor-promoting role of BAG3 in PDAC tumors, suggesting BAG3 might represent an interesting therapeutic opportunity to PDAC patients.
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BAG3 directly stabilizes hexokinase 2 mrna and promotes aerobic glycolysis in pancreatic cancer cells
Journal of Cell Biology, 2017Co-Authors: Huaqin Wang, Mingxin An, Jiamei Wang, Xiaona Meng, Xinyu Li, Si Li, Chao LiAbstract:Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.
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BAG3 promotes proliferation of ovarian cancer cells via post transcriptional regulation of skp2 expression
Biochimica et Biophysica Acta, 2017Co-Authors: Jingyi Jiang, Zhihong Zong, Huaqin Wang, Xinyu Li, Chao Li, Ye YuanAbstract:Abstract Bcl-2 associated athanogene 3 (BAG3) contains a modular structure, through which BAG3 interacts with a wide range of proteins, thereby affording its capacity to regulate multifaceted biological processes. BAG3 is often highly expressed and functions as a pro-survival factor in many cancers. However, the oncogenic potential of BAG3 remains not fully understood. The cell cycle regulator, S-phase kinase associated protein 2 (Skp2) is increased in various cancers and plays an important role in tumorigenesis. The current study demonstrated that BAG3 promoted proliferation of ovarian cancer cells via upregulation of Skp2. BAG3 stabilized Skp2 mRNA via its 3′-untranslated region (UTR). The current study demonstrated that BAG3 interacted with Skp2 mRNA. In addition, miR-21-5p suppressed Skp2 expression, which was compromised by forced BAG3 expression. These results indicated that at least some oncogenic functions of BAG3 were mediated through posttranscriptional regulation of Skp2 via antagonizing suppressive action of miR-21-5p in ovarian cancer cells.
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BAG3 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1.
American Journal of Translational Research, 2015Co-Authors: Feng Du, Huaqin Wang, Zhenxian Du, Detian Li, Si Li, Hai-yan Zhang, Tian Wang, Yanqiu WangAbstract:Previously we have demonstrated that Bcl-2-associated athanogene 3 (BAG3) is increased in renal fibrosis using a rat unilateral ureteral obstruction model. The current study investigated the role of BAG3 in renal fibrosis using transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of BAG3 in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of BAG3 induction by shorting hairpin RNA suppressed the expression of ECM proteins but had no effect on PAI-1 expression induced by TGF-β1. Forced overexpression of BAG3 selectively increased collagens. TGF-β1-induced BAG3 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. In addition, forced BAG3 overexpression blocked attenuation of collagens expression by ERK1/2 and JNK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of BAG3, which would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.
Serena Carra - One of the best experts on this subject based on the ideXlab platform.
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TDP25 aggregation in motor neuron and muscle cells is rescued by chaperone overexpression
2018Co-Authors: M.e. Cicardi, Serena Carra, R. Cristofani, P. Rusmini, M. Meroni, V. Ferrari, B. Tedesco, M. Galbiati, V. Crippa, Angelo PolettiAbstract:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving both upper and lower motor neurons (MNs). As target of MNs, muscle cells role in ALS has always been investigated. ALS can appear as familial or sporadic form, and in the vast majority of patients motor neurons have been observed proteinaceous inclusions containing TDP43. TDP43 inside cytoplasmic aggregates has been found cleaved into C-terminal fragments of 35 and 25 kDa highly aggregation prone. In this work we firstly investigate the aggregation propensity of TDP43 and its ALS-associated fragments TDP35 and TDP25 in both motor neuron like (NSC34) and muscle like cells (C2C12). We found that TDP43 forms physiological oligomers retained in filter retardation assay (FRA) due to the interaction of the N-terminal domain in the nucleus. To correctly visualized TDP25 aggregates we used the NP40 extraction, and we observed the greatest fraction of TDP25 isolated in the NP40 insoluble fraction. Then we studied the degradation of TDPs species, noting that they were mainly degraded via proteasome, while autophagy contribution is less important. Targeting the degradation of aggregation-prone species is a promising strategy to counteract ALS and we increase protein degradation by mean of particular chaperones such as Bag1, BAG3 and HspB8. These proteins, in complex with Hsp70, direct cargos alternatively to proteasome (Bag1) or to autophagy (HspB8 and BAG3, in complex). Overexpressing Bag1 we found that both in NSC34 and C2C12 TDP25 aggregation was rescued, due to an increased degradation via the proteasome. Similar results were obtained in both models targeting autophagy by overexpressing HspB8 and BAG3. Concluding, we showed that muscle cells are a site of misfolded protein aggregation as well as MNs. Importantly, we demonstrated that indirectly targeting degradative pathways by overexpressing chaperones could be beneficial against the formation of TDP25 aggregates both in MNs and muscle cells
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An interaction study in mammalian cells demonstrates weak binding of HSPB2 to BAG3, which is regulated by HSPB3 and abrogated by HSPB8
Cell Stress and Chaperones, 2017Co-Authors: Federica F. Morelli, Laura Mediani, Arianna Dorotea Carrà, Ilaria Bigi, Jonathan Vinet, Lonneke Heldens, Jessika Bertacchini, Serena CarraAbstract:The ten mammalian small heat shock proteins (sHSPs/HSPBs) show a different expression profile, although the majority of them are abundant in skeletal and cardiac muscles. HSPBs form hetero-oligomers and homo-oligomers by interacting together and complexes containing, e.g., HSPB2/HSPB3 or HSPB1/HSPB5 have been documented in mammalian cells and muscles. Moreover, HSPB8 associates with the Hsc70/Hsp70 co-chaperone BAG3, in mammalian, skeletal, and cardiac muscle cells. Interaction of HSPB8 with BAG3 regulates its stability and function. Weak association of HSPB5 and HSPB6 with BAG3 has been also reported upon overexpression in cells, supporting the idea that BAG3 might indirectly modulate the function of several HSPBs. However, it is yet unknown whether other HSPBs highly expressed in muscles such as HSPB2 and HSPB3 also bind to BAG3. Here, we report that in mammalian cells, upon overexpression, HSPB2 binds to BAG3 with an affinity weaker than HSPB8. HSPB2 competes with HSPB8 for binding to BAG3. In contrast, HSPB3 negatively regulates HSPB2 association with BAG3. In human myoblasts that express HSPB2, HSPB3, HSPB8, and BAG3, the latter interacts selectively with HSPB8. Combining these data, it supports the interpretation that HSPB8-BAG3 is the preferred interaction.
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BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta implications for a proteasome to autophagy switch
Autophagy, 2014Co-Authors: Melania Minoia, Andrea Boncoraglio, Federica Francesca Morelli, Jeanette F Brunsting, Angelo Poletti, Sabine Krom, Harm H. Kampinga, Eric Reits, Jonathan Vinet, Serena CarraAbstract:Eukaryotic cells use autophagy and the ubiquitin–proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers. Following proteasome inhibition, BAG3 upregulation significantly contributes to the compensatory activation of autophagy and to the degradation of the (poly)ubiquitinated proteins. BAG3 binding to the ubiquitinated clients occurs through the BAG domain, in competition with BAG1, another BAG family member, that normally directs ubiquitinated clients to the proteasome. Therefore, we propose that following proteasome impairment, increasing the BAG3/BAG1 ratio ensures the “BAG-instructed proteasomal to autophagosomal switch and sorting” (BIPASS).
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BAG3 induces the sequestration of proteasomal clients into cytoplasmic puncta implications for a proteasome to autophagy switch
Autophagy, 2014Co-Authors: Melania Minoia, Andrea Boncoraglio, Federica Francesca Morelli, Jeanette F Brunsting, Angelo Poletti, Sabine Krom, Harm H. Kampinga, Eric Reits, Jonathan Vinet, Serena CarraAbstract:Eukaryotic cells use autophagy and the ubiquitin–proteasome system as their major protein degradation pathways. Upon proteasomal impairment, cells switch to autophagy to ensure proper clearance of clients (the proteasome-to-autophagy switch). The HSPA8 and HSPA1A cochaperone BAG3 has been suggested to be involved in this switch. However, at present it is still unknown whether and to what extent BAG3 can indeed reroute proteasomal clients to the autophagosomal pathway. Here, we show that BAG3 induces the sequestration of ubiquitinated clients into cytoplasmic puncta colabeled with canonical autophagy linkers and markers. Following proteasome inhibition, BAG3 upregulation significantly contributes to the compensatory activation of autophagy and to the degradation of the (poly)ubiquitinated proteins. BAG3 binding to the ubiquitinated clients occurs through the BAG domain, in competition with BAG1, another BAG family member, that normally directs ubiquitinated clients to the proteasome. Therefore, we propose that following proteasome impairment, increasing the BAG3/BAG1 ratio ensures the “BAG-instructed proteasomal to autophagosomal switch and sorting” (BIPASS).
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BAG3 directly interacts with mutated alphab crystallin to suppress its aggregation and toxicity
PLOS ONE, 2011Co-Authors: Akinori Hishiya, Mortada Najem Salman, Serena Carra, Harm H. Kampinga, Shinichi TakayamaAbstract:A homozygous disruption or genetic mutation of the BAG3 gene causes progressive myofibrillar myopathy in mouse and human skeletal and cardiac muscle disorder while mutations in the small heat shock protein αB-crystallin gene (CRYAB) are reported to be responsible for myofibrillar myopathy. Here, we demonstrate that BAG3 directly binds to wild-type αB-crystallin and the αB-crystallin mutant R120G, via the intermediate domain of BAG3. Peptides that inhibit this interaction in an in vitro binding assay indicate that two conserved Ile-Pro-Val regions of BAG3 are involved in the interaction with αB-crystallin, which is similar to results showing BAG3 binding to HspB8 and HspB6. BAG3 overexpression increased αB-crystallin R120G solubility and inhibited its intracellular aggregation in HEK293 cells. BAG3 suppressed cell death induced by αB-crystallin R120G overexpression in differentiating C2C12 mouse myoblast cells. Our findings indicate a novel function for BAG3 in inhibiting protein aggregation caused by the genetic mutation of CRYAB responsible for human myofibrillar myopathy.
Alessandra Rosati - One of the best experts on this subject based on the ideXlab platform.
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BAG3 expression correlates with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix
Acta Obstetricia et Gynecologica Scandinavica, 2020Co-Authors: Antonio Raffone, Antonio Travaglino, Margot De Marco, Miriam Caccese, Antonio Dantonio, Pio Zeppa, Massimo Mascolo, Luigi Insabato, Alessandra Rosati, Antonio MolloAbstract:INTRODUCTION: Bcl-2-associated athanogene 3 (BAG3) is a protein involved in apoptosis and stress response, which is overexpressed in invasive cervical cancer. However, nothing is known about BAG3 expression in precancerous lesions of the uterine cervix. We aimed to evaluate the expression of BAG3 in cervical intraepithelial neoplasia/squamous intraepithelial lesions (CIN/SIL). MATERIAL AND METHODS: Forty patients (16 CIN1/L-SIL, 11 CIN2/H-SIL and 13 CIN3/H-SIL) were assessed by immunohistochemistry for BAG3. The intensity of BAG3 expression was categorized as null, minimal, weak, moderate or strong. The association of BAG2 intensity of expression with the grade of dysplasia was assessed using Chi-square test (significant P value <0.05). RESULTS: In all normal controls, BAG3 expression was negative. In L-SIL specimens, BAG3 expression was confined to the basal third of the epithelium, with an intensity minimal in nine cases (56.3%), weak in six (37.5%) and strong in one (6.3%). In H-SIL specimens, BAG3 expression involved also the two upper thirds of the epithelium, with an intensity moderate in 13 cases (54.2%; 8 CIN2 and 5 CIN3) and strong in 11 cases (45.8%; 3 CIN2 and 8 CIN3). The distribution of BAG3 expression correlated perfectly with the grade of dysplasia (P = 0.0); a moderate/strong expression of BAG3 was significantly associated with H-SIL (P < 0.0001), with no significant difference between CIN2 and CIN3 (P = 0.1228). CONCLUSIONS: In CIN/SIL, both distribution and intensity of BAG3 expression correlate directly with the grade of dysplasia, supporting the involvement of BAG3 in all phases of cervical carcinogenesis and its possible diagnostic and prognostic role in cervical premalignant lesions.
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BAG3 expression correlates with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix
Acta Obstetricia et Gynecologica Scandinavica, 2019Co-Authors: Antonio Raffone, Antonio Travaglino, Antonio D'antonio, Margot De Marco, Miriam Caccese, Pio Zeppa, Massimo Mascolo, Luigi Insabato, Alessandra Rosati, Antonio MolloAbstract:INTRODUCTION: Bcl-2-associated athanogene 3 (BAG3) is a protein involved in apoptosis and stress response, which is overexpressed in invasive cervical cancer. However, nothing is known about BAG3 expression in precancerous lesions of the uterine cervix. We aimed to evaluate the expression of BAG3 in cervical intraepithelial neoplasia/squamous intraepithelial lesions (CIN/SIL). MATERIAL AND METHODS: Forty patients (16 CIN1/L-SIL, 11 CIN2/H-SIL and 13 CIN3/H-SIL) were assessed by immunohistochemistry for BAG3. The intensity of BAG3 expression was categorized as null, minimal, weak, moderate or strong. The association of BAG2 intensity of expression with the grade of dysplasia was assessed using Chi-square test (significant P value
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the prosurvival protein BAG3 a new participant in vascular homeostasis
Cell Death and Disease, 2016Co-Authors: Albino Carrizzo, Antonia Falco, Maria Caterina Turco, Antonio Damato, Mariateresa Ambrosio, Michele Madonna, James L Januzzi, Alessandra Rosati, Mario Capunzo, Vincenzo De LaurenziAbstract:Bcl2-associated athanogene 3 (BAG3), is constitutively expressed in a few normal cell types, including myocytes, peripheral nerves and in the brain, and is also expressed in certain tumors. To date, the main studies about the role of BAG3 are focused on its pro-survival effect in tumors through various mechanisms that vary according to cellular type. Recently, elevated concentrations of a soluble form of BAG3 were described in patients affected by advanced stage of heart failure (HF), identifying BAG3 as a potentially useful biomarker in monitoring HF progression. Despite the finding of high levels of BAG3 in the sera of HF patients, there are no data on its possible role on the modulation of vascular tone and blood pressure levels. The aim of this study was to investigate the possible hemodynamic effects of BAG3 performing both in vitro and in vivo experiments. Through vascular reactivity studies, we demonstrate that BAG3 is capable of evoking dose-dependent vasorelaxation. Of note, BAG3 exerts its vasorelaxant effect on resistance vessels, typically involved in the blood pressure regulation. Our data further show that the molecular mechanism through which BAG3 exerts this effect is the activation of the PI3K/Akt signalling pathway leading to nitric oxide release by endothelial cells. Finally, we show that in vivo BAG3 administration is capable of regulating blood pressure and that this is dependent on eNOS regulation since this ability is lost in eNOS KO animals.
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analysis of BAG3 plasma concentrations in patients with acutely decompensated heart failure
Clinica Chimica Acta, 2015Co-Authors: Parul U Gandhi, Anna Basile, Antonia Falco, Hanna K Gaggin, Arianna M Belcher, Jamie Harisiades, Federico Piscione, James L Januzzi, Alessandra Rosati, Caterina M TurcoAbstract:Abstract Background BCL-2-associated athanogene 3 (BAG3) is a protein implicated in the cardiomyocyte stress response and genesis of cardiomyopathy. Extracellular BAG3 is measurable in patients with heart failure (HF), but the relationship of BAG3 with HF prognosis is unclear. Methods BAG3 plasma concentrations were measured in 39 acutely decompensated HF patients; the primary endpoint was death at 1 year. Baseline characteristics were compared by vital status and median BAG3 concentration. Correlation of BAG3 with left ventricular ejection fraction (LVEF) and other biomarkers was performed. Prognostic value was assessed using Cox proportional hazards regression and Kaplan–Meier analysis. Results At baseline, median BAG3 was significantly higher in decedents (N = 11) than survivors (N = 28; 1489 ng/mL versus 50 ng/mL; P = 0.04); decedents also had worse renal function and higher median natriuretic peptide (NP) and sST2. BAG3 was not significantly correlated with NPs, mid-regional pro-adrenomedullin, sST2, or eGFR, however. Mortality was increased in patients with supra-median BAG3 (> 336 ng/mL; 42.1% versus 15.0%, P = 0.06). In age and LVEF-adjusted Cox proportional hazards, BAG3 remained a significant mortality predictor (HR = 3.20; 95% CI = 1.34–7.65; P = 0.02); those with supra-median BAG3 had significantly shorter time-to-death (P = 0.04). Conclusion The stress response protein BAG3 is measurable in patients with ADHF and may be prognostic for death.
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ww domain of BAG3 is required for the induction of autophagy in glioma cells
Journal of Cellular Physiology, 2015Co-Authors: Nana Merabova, Ilker Kudret Sariyer, Sami A Saribas, Tijana Knezevic, Caterina M Turco, Michael T. Weaver, Jacques Landry, Alessandra Rosati, Jennifer Gordon, Kamel KhaliliAbstract:Autophagy is an evolutionarily conserved, selective degradation pathway of cellular components that is important for cell homeostasis under healthy and pathologic conditions. Here we demonstrate that an increase in the level of BAG3 results in stimulation of autophagy in glioblastoma cells. BAG3 is a member of a co-chaperone family of proteins that associate with Hsp70 through a conserved BAG domain positioned near the C-terminus of the protein. Expression of BAG3 is induced by a variety of environmental changes that cause stress to cells. Our results show that BAG3 overexpression induces autophagy in glioma cells. Interestingly, inhibition of the proteasome caused an increase in BAG3 levels and induced autophagy. Further analysis using specific siRNA against BAG3 suggests that autophagic activation due to proteosomal inhibition is mediated by BAG3. Analyses of BAG3 domain mutants suggest that the WW domain of BAG3 is crucial for the induction of autophagy. BAG3 overexpression also increased the interaction between Bcl2 and Beclin-1, instead of disrupting them, suggesting that BAG3 induced autophagy is Beclin-1 independent. These observations reveal a novel role for the WW domain of BAG3 in the regulation of autophagy.
Kamel Khalili - One of the best experts on this subject based on the ideXlab platform.
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Evidence for the impact of BAG3 on electrophysiological activity of primary culture of neonatal cardiomyocytes
Journal of Cellular Physiology, 2019Co-Authors: Farzaneh G Tahrir, Arthur M Feldman, Kamel Khalili, Jennifer Gordon, Joseph Y Cheung, Taha Mohseni AhooyiAbstract:: Homeostasis of proteins involved in contractility of individual cardiomyocytes and those coupling adjacent cells is of critical importance as any abnormalities in cardiac electrical conduction may result in cardiac irregular activity and heart failure. Bcl2-associated athanogene 3 (BAG3) is a stress-induced protein whose role in stabilizing myofibril proteins as well as protein quality control pathways, especially in the cardiac tissue, has captured much attention. Mutations of BAG3 have been implicated in the pathogenesis of cardiac complications such as dilated cardiomyopathy. In this study, we have used an in vitro model of neonatal rat ventricular cardiomyocytes to investigate potential impacts of BAG3 on electrophysiological activity by employing the microelectrode array (MEA) technology. Our MEA data showed that BAG3 plays an important role in the cardiac signal generation as reduced levels of BAG3 led to lower signal frequency and amplitude. Our analysis also revealed that BAG3 is essential to the signal propagation throughout the myocardium, as the MEA data-based conduction velocity, connectivity degree, activation time, and synchrony were adversely affected by BAG3 knockdown. Moreover, BAG3 deficiency was demonstrated to be connected with the emergence of independently beating clusters of cardiomyocytes. On the other hand, BAG3 overexpression improved the activity of cardiomyocytes in terms of electrical signal amplitude and connectivity degree. Overall, by providing more in-depth analyses and characterization of electrophysiological parameters, this study reveals that BAG3 is of critical importance for electrical activity of neonatal cardiomyocytes.
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evidence for the role of BAG3 in mitochondrial quality control in cardiomyocytes
Journal of Cellular Physiology, 2017Co-Authors: Farzaneh G Tahrir, Tijana Knezevic, Arthur M Feldman, Jennifer Gordon, Joseph Y Cheung, Manish K Gupta, Kamel KhaliliAbstract:: Mitochondrial abnormalities impact the development of myofibrillar myopathies. Therefore, understanding the mechanisms underlying the removal of dysfunctional mitochondria from cells is of great importance toward understanding the molecular events involved in the genesis of cardiomyopathy. Earlier studies have ascribed a role for BAG3 in the development of cardiomyopathy in experimental animals leading to the identification of BAG3 mutations in patients with heart failure which may play a part in the onset of disease development and progression. BAG3 is co-chaperone of heat shock protein 70 (HSP70), which has been shown to modulate apoptosis and autophagy, in several cell models. In this study, we explore the potential role of BAG3 in mitochondrial quality control. We demonstrate that siRNA mediated suppression of BAG3 production in neonatal rat ventricular cardiomyocytes (NRVCs) significantly elevates the level of Parkin, a key component of mitophagy. We found that both BAG3 and Parkin are recruited to depolarized mitochondria and promote mitophagy. Suppression of BAG3 in NRVCs significantly reduces autophagy flux and eliminates clearance of Tom20, an essential import receptor for mitochondria proteins, after induction of mitophagy. These observations suggest that BAG3 is critical for the maintenance of mitochondrial homeostasis under stress conditions, and disruptions in BAG3 expression impact cardiomyocyte function. J. Cell. Physiol. 232: 797-805, 2017. © 2016 Wiley Periodicals, Inc.
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Evidence for the Role of BAG3 in Mitochondrial Quality Control in Cardiomyocytes.
Journal of Cellular Physiology, 2016Co-Authors: Farzaneh G Tahrir, Tijana Knezevic, Arthur M Feldman, Jennifer Gordon, Joseph Y Cheung, Manish K Gupta, Kamel KhaliliAbstract:Abstract Mitochondrial abnormalities impact the development of myofibrillar myopathies. Therefore, understanding the mechanisms underlying the removal of dysfunctional mitochondria from cells is of great importance toward understanding the molecular events involved in the genesis of cardiomyopathy. Earlier studies have ascribed a role for BAG3 in the development of cardiomyopathy in experimental animals leading to the identification of BAG3 mutations in patients with heart failure which may play a part in the onset of disease development and progression. BAG3 is co-chaperone of heat shock protein 70 (HSP70), which has been shown to modulate apoptosis and autophagy, in several cell models. In this study, we explore the potential role of BAG3 in mitochondrial quality control. We demonstrate that siRNA mediated suppression of BAG3 production in neonatal rat ventricular cardiomyocytes (NRVCs) significantly elevates the level of Parkin, a key component of mitophagy. We found that both BAG3 and Parkin are recruited to depolarized mitochondria and promote mitophagy. Suppression of BAG3 in NRVCs significantly reduces autophagy flux and eliminates expression of Tom20, an essential import receptor for mitochondria proteins, after induction of mitophagy. These observations suggest that BAG3 is critical for the maintenance of mitochondrial homeostasis under stress conditions, and disruptions in BAG3 expression impact cardiomyocyte function. This article is protected by copyright. All rights reserved.
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ww domain of BAG3 is required for the induction of autophagy in glioma cells
Journal of Cellular Physiology, 2015Co-Authors: Nana Merabova, Ilker Kudret Sariyer, Sami A Saribas, Tijana Knezevic, Caterina M Turco, Michael T. Weaver, Jacques Landry, Alessandra Rosati, Jennifer Gordon, Kamel KhaliliAbstract:Autophagy is an evolutionarily conserved, selective degradation pathway of cellular components that is important for cell homeostasis under healthy and pathologic conditions. Here we demonstrate that an increase in the level of BAG3 results in stimulation of autophagy in glioblastoma cells. BAG3 is a member of a co-chaperone family of proteins that associate with Hsp70 through a conserved BAG domain positioned near the C-terminus of the protein. Expression of BAG3 is induced by a variety of environmental changes that cause stress to cells. Our results show that BAG3 overexpression induces autophagy in glioma cells. Interestingly, inhibition of the proteasome caused an increase in BAG3 levels and induced autophagy. Further analysis using specific siRNA against BAG3 suggests that autophagic activation due to proteosomal inhibition is mediated by BAG3. Analyses of BAG3 domain mutants suggest that the WW domain of BAG3 is crucial for the induction of autophagy. BAG3 overexpression also increased the interaction between Bcl2 and Beclin-1, instead of disrupting them, suggesting that BAG3 induced autophagy is Beclin-1 independent. These observations reveal a novel role for the WW domain of BAG3 in the regulation of autophagy.
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HIV-1 Tat protein induces glial cell autophagy through enhancement of BAG3 protein levels
Cell Cycle, 2014Co-Authors: Anna Paola Bruno, Ilker Kudret Sariyer, Margot De Marco, Stefania Lucia Nori, Francesca Isabella De Simone, Kamel Khalili, Vittoria Iorio, Mario Capunzo, Alessandra RosatiAbstract:BAG3 protein has been described as an anti-apoptotic and pro-autophagic factor in several neoplastic and normal cells. We previously demonstrated that BAG3 expression is elevated upon HIV-1 infection of glial and T lymphocyte cells. Among HIV-1 proteins, Tat is highly involved in regulating host cell response to viral infection. Therefore, we investigated the possible role of Tat protein in modulating BAG3 protein levels and the autophagic process itself. In this report, we show that transfection with Tat raises BAG3 levels in glioblastoma cells. Moreover, BAG3 silencing results in highly reducing Tat- induced levels of LC3-II and increasing the appearance of sub G0/G1 apoptotic cells, in keeping with the reported role of BAG3 in modulating the autophagy/apoptosis balance. These results demonstrate for the first time that Tat protein is able to stimulate autophagy through increasing BAG3 levels in human glial cells.
Christian Behl - One of the best experts on this subject based on the ideXlab platform.
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breaking bag the co chaperone BAG3 in health and disease
Trends in Pharmacological Sciences, 2016Co-Authors: Christian BehlAbstract:Human BAG ( B cl-2-associated a thano g ene) proteins form a family of antiapoptotic proteins that currently consists of six members (BAG1–6) all sharing the BAG protein domain from which the name arises. Via this domain, BAG proteins bind to the heat shock protein 70 (Hsp70), thereby acting as a co-chaperone regulating the activity of Hsp70. In addition to their antiapoptotic activity, all human BAG proteins have distinct functions in health and disease, and BAG3 in particular is the focus of many investigations. BAG3 has a modular protein domain composition offering the possibility for manifold interactions with other proteins. Various BAG3 functions are implicated in disorders including cancer, myopathies, and neurodegeneration. The discovery of its role in selective autophagy and the description of BAG3-mediated selective macroautophagy as an adaptive mechanism to maintain cellular homeostasis, under stress as well as during aging, make BAG3 a highly interesting target for future pharmacological interventions.
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Proteomic Analysis Reveals a Role for Bcl2-associated Athanogene 3 and Major Vault Protein in Resistance to Apoptosis in Senescent Cells by Regulating ERK1/2 Activation
Molecular & Cellular Proteomics, 2014Co-Authors: Martina P. Pasillas, Christian Behl, Sarah Shields, Rebecca Reilly, Jan Strnadel, Robin Park, John R. Yates, Richard L. Klemke, Steven L. Gonias, Judith A. CoppingerAbstract:Senescence is a prominent solid tumor response to therapy in which cells avoid apoptosis and instead enter into prolonged cell cycle arrest. We applied a quantitative proteomics screen to identify signals that lead to therapy-induced senescence and discovered that Bcl2-associated athanogene 3 (BAG3) is up-regulated after adriamycin treatment in MCF7 cells. BAG3 is a member of the BAG family of co-chaperones that interacts with Hsp70. BAG3 also regulates major cell-signaling pathways. Mass spectrometry analysis of the BAG3 Complex revealed a novel interaction between BAG3 and Major Vault Protein (MVP). Silencing of BAG3 or MVP shifts the cellular response to adriamycin to favor apoptosis. We demonstrate that BAG3 and MVP contribute to apoptosis resistance in therapy-induced senescence by increasing the level of activation of extracellular signal-regulated kinase1/2 (ERK1/2). Silencing of either BAG3 or MVP decreased ERK1/2 activation and promoted apoptosis in adriamycin-treated cells. An increase in nuclear accumulation of MVP is observed during therapy-induced senescence and the shift in MVP subcellular localization is BAG3-dependent. We propose a model in which BAG3 binds to MVP and facilitates MVP accumulation in the nucleus, which sustains ERK1/2 activation. We confirmed that silencing of BAG3 or MVP shifts the response toward apoptosis and regulates ERK1/2 activation in a panel of diverse breast cancer cell lines. This study highlights BAG3-MVP as an important complex that regulates a potent prosurvival signaling pathway and contributes to chemotherapy resistance in breast cancer.
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BAG3 and friends co chaperones in selective autophagy during aging and disease
Autophagy, 2011Co-Authors: Christian BehlAbstract:There is a reciprocal change in the expression of two members of the BAG (Bcl-2-associated athanogen) family, BAG1 and BAG3, during cellular aging and under acute stress ("BAG1-BAG3-switch"). BAG3 was recently described as a mediator of a novel macroautophagy pathway that uses the specificity of heat shock protein 70 (HSP70) to misfolded proteins and also involves other protein partners, such as HSPB8. Also crucial for induction and execution of autophagy are sequestosome-1/p62 (SQSTM1/p62) and LC3, an autophagosome-associated protein. In this novel pathway, BAG3 mediates the targeting and transport of degradation-prone substrates into aggresomes via the microtubule-motor dynein. Interestingly, aggresome-targeting by BAG3 does not depend on substrate ubiquitination and is, therefore, involved in the clearance of misfolded proteins that are not ubiquitinated.
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Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3
The EMBO Journal, 2009Co-Authors: Martin Gamerdinger, Parvana Hajieva, A Murat Kaya, F. Ulrich Hartl, Uwe Wolfrum, Christian BehlAbstract:The Hsc/Hsp70 co-chaperones of the BAG (Bcl-2-associated athanogene) protein family are modulators of protein quality control. We examined the specific roles of BAG1 and BAG3 in protein degradation during the aging process. We show that BAG1 and BAG3 regulate proteasomal and macroautophagic pathways, respectively, for the degradation of polyubiquitinated proteins. Moreover, using models of cellular aging, we find that a switch from BAG1 to BAG3 determines that aged cells use more intensively the macroautophagic system for turnover of polyubiquitinated proteins. This increased macroautophagic flux is regulated by BAG3 in concert with the ubiquitin-binding protein p62/SQSTM1. The BAG3/BAG1 ratio is also elevated in neurons during aging of the rodent brain, where, consistent with a higher macroautophagy activity, we find increased levels of the autophagosomal marker LC3-II as well as a higher cathepsin activity. We conclude that the BAG3-mediated recruitment of the macroautophagy pathway is an important adaptation of the protein quality control system to maintain protein homeostasis in the presence of an enhanced pro-oxidant and aggregation-prone milieu characteristic of aging.
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Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution,andreproductioninanymed
2009Co-Authors: Martin Gamerdinger, Parvana Hajieva, A Murat Kaya, F. Ulrich Hartl, Uwe Wolfrum, Christian BehlAbstract:The Hsc/Hsp70 co-chaperones of the BAG (Bcl-2-associated athanogene) protein family are modulators of protein quality control. We examined the specific roles of BAG1 and BAG3 in protein degradation during the aging process. We show that BAG1 and BAG3 regulate proteasomal and macroautophagic pathways, respectively, for the degradation of polyubiquitinated proteins. Moreover, using models of cellular aging, we find that a switch from BAG1 to BAG3 determines that aged cells use more intensively the macroautophagic system for turnover of polyubiquitinated proteins. This increased macroautophagic flux is regulated by BAG3 in concert with the ubiquitin-binding protein p62/SQSTM1. The BAG3/BAG1 ratio is also elevated in neurons during aging of the rodent brain, where, consistent with a higher macroautophagy activity, we find increased levels of the autophagosomal marker LC3-II as well as a higher cathepsin activity. We conclude that the BAG3-mediated recruitment of the macroautophagy pathway is an important adaptation of the protein quality control system to maintain protein homeostasis in the presence of an enhanced pro-oxidant and aggregationprone milieu characteristic of aging.
