scholarly journals NOP53 Suppresses Autophagy through ZKSCAN3-Dependent and -Independent Pathways

2021 ◽  
Vol 22 (17) ◽  
pp. 9318
Author(s):  
Young-Eun Cho ◽  
Yong-Jun Kim ◽  
Sun Lee ◽  
Jae-Hoon Park
Keyword(s):  
Histone H3 ◽  
Nucleolar Protein ◽  
Autophagic Flux ◽  
Phosphatidylinositol 3 Kinase ◽  
Upstream Regulator ◽  
Multistep Process ◽  
Nuclear Events ◽  
Stress Sensing ◽  
Related Proteins ◽  
Dependent Pathway

Autophagy is an evolutionally conserved process that recycles aged or damaged intracellular components through a lysosome-dependent pathway. Although this multistep process is propagated in the cytoplasm by the orchestrated activity of the mTOR complex, phosphatidylinositol 3-kinase, and a set of autophagy-related proteins (ATGs), recent investigations have suggested that autophagy is tightly regulated by nuclear events. Thus, it is conceivable that the nucleolus, as a stress-sensing and -responding intranuclear organelle, plays a role in autophagy regulation, but much is unknown concerning the nucleolar controls in autophagy. In this report, we show a novel nucleolar–cytoplasmic axis that regulates the cytoplasmic autophagy process: nucleolar protein NOP53 regulates the autophagic flux through two divergent pathways, the ZKSCAN3-dependent and -independent pathways. In the ZKSCAN3-dependent pathway, NOP53 transcriptionally activates a master autophagy suppressor ZKSCAN3, thereby inhibiting MAP1LC3B/LC3B induction and autophagy propagation. In the ZKSCAN3-independent pathway, NOP53 physically interacts with histone H3 to dephosphorylate S10 of H3, which, in turn, transcriptionally downregulates the ATG7 and ATG12 expressions. Our results identify nucleolar protein NOP53 as an upstream regulator of the autophagy process.

scholarly journals Acylated Ghrelin is Protective Against 6-OHDA-induced Neurotoxicity by Regulating Autophagic Flux

2021 ◽  
Vol 11 ◽  
Author(s):  
Xin He ◽  
Wei Yuan ◽  
Fei Liu ◽  
Juan Feng ◽  
Yanxia Guo
Keyword(s):  
Neurodegenerative Disorders ◽  
Caspase 3 ◽  
Cell Model ◽  
Autophagic Flux ◽  
Acylated Ghrelin ◽  
Neuron Death ◽  
Upstream Regulator ◽  
The Central Nervous System ◽  
And Function ◽  
Related Proteins

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, and our previous study revealed that autophagic flux dysfunction contributes to the neuron death in 6-OHDA-induced PD models. Acylated ghrelin is a neuropeptide that has a variety of actions in the central nervous system. In the current study, we aimed to investigate whether ghrelin is neuroprotective in 6-OHDA-induced rat model and SH-SY5Y cell model and whether it is related to autophagic flux regulation. We observed that ghrelin could effectively reduce apomorphine-induced contralateral rotation in 6-OHDA-induced PD rats, preserve the expression of tyrosine hydroxylase (TH) and increase the cell viability. It could upregulate the expression of autophagy related proteins like Atg7 and LC3-II and downregulate p62, and downregulate apoptosis related proteins like bax and cleaved caspase 3. SH-SY5Y cells transfected with adenovirus Ad-mCherry-GFP-LC3B further revealed that ghrelin could relieve the autophagic flux dysfunction induced by 6-OHDA. Lysotracker staining showed that ghrelin could reverse the decrease in lysosomes induced by 6-OHDA and immunofluorescence staining revealed a reverse of TFEB level in SH-SY5Y cells. Blocking autophagy activation with 3-methyladenine (3-MA) in rats treated with ghrelin and 6-OHDA showed no notable change in apoptosis-related markers, while blocking autophagosome fusion with lysosomes with chloroquine could notably reverse the downregulation of bax/bcl-2 ratio and cleaved caspase three expression by ghrelin. Additionally, knockdown ATG7, the upstream regulator of autophagy, with siRNA could further decrease the number of apoptotic cells in SH-SY5Y cells exposed to 6-OHDA and treated with ghrelin, while knockdown TFEB, a key transcription factor for lysosome biosynthesis and function, with siRNA could completely abolish the anti-apoptosis effect of ghrelin. These data suggest that ghrelin is neuroprotective in 6-OHDA-induced PD models via improving autophagic flux dysfunction and restoration of TFEB level.

scholarly journals A reversible autophagy inhibitor blocks autophagosome–lysosome fusion by preventing Stx17 loading onto autophagosomes

2019 ◽  
Vol 30 (17) ◽  
pp. 2283-2295 ◽  
Author(s):  
Somya Vats ◽  
Ravi Manjithaya
Keyword(s):  
Egf Receptor ◽  
De Novo ◽  
Degradation Pathway ◽  
Vesicular Trafficking ◽  
Autophagic Flux ◽  
Lysosomal Degradation ◽  
Evolutionarily Conserved ◽  
Multistep Process ◽  
Novel Method ◽  
Related Proteins

Autophagy is an evolutionarily conserved intracellular lysosomal degradation pathway. It is a multistep process involving de novo formation of double membrane autophagosomes that capture cytosolic constituents (cargo) and eventually fuse with lysosomes wherein the cargo gets degraded and resulting simpler biomolecules get recycled. In addition to their autophagy function, several of the autophagy-related proteins work at the interface of other vesicular trafficking pathways. Hence, development of specific autophagy modulators that do not perturb general endo-lysosomal traffic possesses unique challenges. In this article, we report a novel small molecule EACC that inhibits autophagic flux by blocking autophagosome–lysosome fusion. Strikingly, unlike other late stage inhibitors, EACC does not have any effect on lysosomal properties or on endocytosis-mediated degradation of EGF receptor. EACC affects the translocation of SNAREs Stx17 and SNAP29 on autophagosomes without impeding the completion of autophagosomes. EACC treatment also reduces the interaction of Stx17 with the HOPS subunit VPS33A and the cognate lysosomal R-SNARE VAMP8. Interestingly, this effect of EACC although quite robust is reversible and hence EACC can be used as a tool to study autophagosomal SNARE trafficking. Our results put forward a novel method to block autophagic flux by impeding the action of the autophagosomal SNAREs.

scholarly journals Semaphorin 7A plays a critical role in TGF-β1–induced pulmonary fibrosis

2007 ◽  
Vol 204 (5) ◽  
pp. 1083-1093 ◽  
Author(s):  
Hye-Ryun Kang ◽  
Chun Geun Lee ◽  
Robert J. Homer ◽  
Jack A. Elias
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Matrix Proteins ◽  
Ccn Proteins ◽  
Phosphatidylinositol 3 Kinase ◽  
Smad 3 ◽  
Dependent Pathway ◽  
Tgf Β1

Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-β1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-β1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-β1, highlighting the importance of these findings for other fibrotic stimuli.

scholarly journals Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

2021 ◽  
Author(s):  
Qian-Qian Sha ◽  
Ye-Zhang Zhu ◽  
Yunlong Xiang ◽  
Jia-Li Yu ◽  
Xiao-Ying Fan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone H3 ◽  
Finger Protein ◽  
Maternal Genome ◽  
Wide Range ◽  
Transcriptional Changes ◽  
Nuclear Events ◽  
Genomic Regions ◽  
Cxxc Finger Protein 1

Abstract During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)-Exosome Carrying MiRNA-312 Inhibits Sevoflurane-Induced Cardiomyocyte Apoptosis Through Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B (PI3K/AKT) Pathway

2022 ◽  
Vol 12 (5) ◽  
pp. 947-952
Author(s):  
Jun Zhang ◽  
Yuying Gao ◽  
Peng Chen ◽  
Yu Zhou ◽  
Sheng Guo ◽  
...  
Keyword(s):  
Protein Kinase B ◽  
Cardiomyocyte Apoptosis ◽  
Erk Signaling ◽  
Akt Pathway ◽  
Cardiomyocyte Proliferation ◽  
Akt Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Dmso Treatment ◽  
Induced Apoptosis ◽  
Related Proteins

This study was to explore the mechanism by how exosomes (exo) derived from BMSCs affects cardiomyocyte apoptosis. BMSCs were isolated and incubated with cardiomyocytes while the cardiomyocytes were exposed to sevoflurane or DMSO treatment. Apoptotic cells were calculated and level of apoptosis related proteins was detected by Western blot. Through transfection with microRNA-(miRNA)-312 inhibitor, we evaluated the effect of BMSC-exo on the sevoflurane-induced apoptosis. Sevoflurane significantly inhibited the viability of cardiomyocytes and induced cardiomyocyte apoptosis. Besides, sevoflurane decreased the expression of miR-312 and enhanced Bax expression in cardiomyocytes through restraining the phosphorylation of MAPK/ERK. Treatment with BMSC-exo, however, activated MAPK/ERK signaling by up-regulating miR-312, thereby inhibiting cardiomyocyte apoptosis, promoting cardiomyocyte proliferation, and elevating the level of Bcl-2. In conclusion, BMSC-exo-derived miR-312 inhibits sevoflurane-induced cardiomyocyte apoptosis by activating PI3K/AKT signaling pathway.

scholarly journals Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells

2008 ◽  
Vol 29 (2) ◽  
pp. 559-569 ◽  
Author(s):  
Vladimir L. Gabai ◽  
Julia A. Yaglom ◽  
Todd Waldman ◽  
Michael Y. Sherman
Keyword(s):  
Heat Shock ◽  
Epithelial Cells ◽  
Heat Shock Protein ◽  
Cancer Cells ◽  
Pi3k Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
P53 Pathway ◽  
Extracellular Signal ◽  
Kinase Cascade ◽  
Dependent Pathway

ABSTRACT The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its levels often correlate with poor prognosis. Previously we reported that knockdown of Hsp72 in certain cancer cells, but not in untransformed breast epithelial cells, triggers senescence via p53-dependent and p53-independent mechanisms. Here we demonstrate that the p53-dependent pathway controlled by Hsp72 depends on the oncogenic form of phosphatidylinositol 3-kinase (PI3K). Indeed, upon expression of the oncogenic PI3K, epithelial cells began responding to Hsp72 depletion by activating the p53 pathway. Moreover, in cancer cell lines, activation of the p53 pathway caused by depletion of Hsp72 was dependent on oncogenes that activate the PI3K pathway. On the other hand, the p53-independent senescence pathway controlled by Hsp72 was associated with the Ras oncogene. In this pathway, extracellular signal-regulated kinases (ERKs) were critical for senescence, and Hsp72 controlled the ERK-activating kinase cascade at the level of Raf-1. Importantly, upon Ras expression, untransformed cells started responding to knockdown of Hsp72 by constitutive activation of ERKs, culminating in senescence. Therefore, Hsp72 is intimately involved in suppression of at least two separate senescence signaling pathways that are regulated by distinct oncogenes in transformed cells, which explains why cancer cells become “addicted” to this heat shock protein.

P3485Autophagy insufficiency participates in hyperhomocysteinemia-induced cardiac aging

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
W Wang ◽  
Y Zhou ◽  
J Xu ◽  
S Zhang ◽  
Y Meng
Keyword(s):  
Cardiac Function ◽  
Rat Model ◽  
Natural Aging ◽  
Autophagic Flux ◽  
Cardiac Aging ◽  
Transmission Electron ◽  
Injured Myocardium ◽  
Underlying Mechanisms ◽  
Fdg Pet Ct ◽  
Related Proteins

Abstract Background The elevated plasma homocysteine (Hcy) level can lead to severe cardiovascular injuries, which participates in the progression of atherosclerosis, heart failure and so on. Except cardiovascular diseases, accumulated researches further revealed that hyperhomocystenemia (HHcy) can also induce aging-related diseases, including Alzheimer's disease, Parkinson's disease, diabetic cardiomyopathy, etc. Though some researches had revealed that Hcy stimulation would lead to endothelial cells senescence, whether cardiac aging could be induced by HHcy still remain unknown. Purpose This study aimed to reveal whether HHcy can induce cardiac aging and the underlying mechanisms. Methods SD rats were utilized to establish HHcy rat model and natural aging rat model. The cardiac function were determined by Echocardiography. Transmission electron microscope were used to detect mitochondria injuries of myocardium. 18F-FDG PET/CT was used to detect the state of glucose metabolism in myocardial cells. Agilent mRNA Array was used to detect possible altered pathways in myocardium of HHcy rats. The autophagy level was determined by detection of both autophagy-related proteins expressions with Western Blot and autophagic flux with mRFP-GFP-LC3. Results HHcy rats showed overall aging phenotypes, which were consistent with natural aging rats. The impaired cardiac function and severely injured myocardium morphology were observed in HHcy rats. Aging-related markers were increased significantly in HHcy rats and Hcy-treated cells, presented as increased p16, p21 and p53 expressions and increased senescence-associated beta-galactosidase (SA-β-gal) activity. Mitochondria dysfunction and morphology injuries were also detected in HHcy rats. Moreover, decreased serum Beclin-1 level was tested in CHD patients with HHcy. The decreased autophagy level was further verified in HHcy rats and Hcy-treated cells. Furthermore, the over-expression of Atg5 could attenuate Hcy induced cellular senescence. Conclusion HHcy can reduce autophagy level, which leading to severe mitochondria injuries, and resulted in cardiac aging eventually. Acknowledgement/Funding Natural Science Foundation of China (81671382,91839107)

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