scholarly journals AMBRA1 promotes apoptosis induced by dsRNA and virus through interacting with and stabilizing MAVS

2021 ◽  
Author(s):  
Yuxia Lin ◽  
Changbai Huang ◽  
Huixin Gao ◽  
Xiaobo Li ◽  
Quanshi Lin ◽  
...  
Keyword(s):  
Viral Infection ◽  
Cellular Response ◽  
Semliki Forest Virus ◽  
Mitochondrial Localization ◽  
Apoptosis Pathway ◽  
Mitochondrial Antiviral Signaling ◽  
Induced Apoptosis ◽  
The Impact ◽  
Mitochondrial Antiviral Signaling Protein

Apoptosis is an important cellular response to viral infection. In current study, we identified activating molecule in Beclin1-regulated autophagy protein 1 (AMBRA1) as a positive regulator of apoptosis triggered by dsRNA. Depletion of AMBRA1 by gene editing significantly reduced dsRNA-induced apoptosis, which was largely restored by trans-complementation of AMBRA1. Mechanistically, AMBRA1 interacts with mitochondrial antiviral-signaling protein (MAVS), a key mitochondrial adaptor in the apoptosis pathway induced by dsRNA and viral infection. Further Co-IP analysis demonstrated that the mitochondrial localization of MAVS was essential for their interaction. The impact of AMBRA1 on dsRNA-induced apoptosis relied on the presence of MAVS and caspase-8. AMBRA1 was involved in the stabilization of MAVS through preventing its proteasomal degradation induced by dsRNA. Consistently, AMBRA1 upregulated the apoptosis induced by Semliki Forest virus infection. Taken together, our work illustrated a role of AMBRA1 in the virus-induced apoptosis through interacting with and stabilizing MAVS.

scholarly journals Role of FoxO Proteins in Cellular Response to Antitumor Agents

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 90 ◽  
Author(s):  
Giovanni Luca Beretta ◽  
Cristina Corno ◽  
Nadia Zaffaroni ◽  
Paola Perego
Keyword(s):  
Drug Resistance ◽  
Transcription Factors ◽  
Cellular Response ◽  
Antitumor Agents ◽  
Antitumor Agent ◽  
Dna Interaction ◽  
Nuclear Retention ◽  
Induced Apoptosis ◽  
The Impact

FoxO proteins (FoxOs) are transcription factors with a common DNA binding domain that confers selectivity for DNA interaction. In human cells, four proteins (FoxO1, FoxO3, FoxO4 and FoxO6), with redundant activity, exhibit mainly a positive effect on genes involved in cell cycle, apoptosis regulation and drug resistance. Thus, FoxOs can affect cell response to antitumor agent treatment. Their transcriptional activity depends on post-translational modifications, including phosphorylation, acetylation, and mono/poly-ubiquitination. Additionally, alterations in microRNA network impact on FoxO transcripts and in turn on FoxO levels. Reduced expression of FoxO1 has been associated with resistance to conventional agents (e.g., cisplatin) and with reduced efficacy of drug combinations in ovarian carcinoma cells. FoxO3 has been shown as a mediator of cisplatin toxicity in colorectal cancer. A requirement for FoxO3-induced apoptosis has been reported in cells exposed to targeted agents (e.g., gefitinib). Recently, the possibility to interfere with FoxO1 localization has been proposed as a valuable approach to improve cell sensitivity to cisplatin, because nuclear retention of FoxO1 may favor the induction of pro-apoptotic genes. This review focuses on the role of FoxOs in drug treatment response in tumor cells and discusses the impact of the expression of these transcription factors on drug resistance/sensitivity.

scholarly journals Autophagy plays a protective role during Pseudomonas aeruginosa-induced apoptosis via ROS–MAPK pathway

2020 ◽  
Vol 26 (7) ◽  
pp. 580-591
Author(s):  
Lu Han ◽  
Qinmei Ma ◽  
Jialin Yu ◽  
Zhaoqian Gong ◽  
Chenjie Ma ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mapk Pathway ◽  
Protective Role ◽  
Vital Role ◽  
Raw264.7 Cells ◽  
Cellular Reactive Oxygen Species ◽  
Induced Apoptosis ◽  
Related Proteins ◽  
The Impact

Pseudomonas aeruginosa infection can induce alveolar macrophage apoptosis and autophagy, which play a vital role in eliminating pathogens. These two processes are usually not independent. Recently, autophagy has been found to interact with apoptosis during pathogen infections. Nevertheless, the role of autophagy in P. aeruginosa-infected cell apoptosis is unclear. In this study, we explored the impact of P. aeruginosa infection on autophagy and apoptosis in RAW264.7 cells. The autophagy activator rapamycin was used to stimulate autophagy and explore the role of autophagy on apoptosis in P. aeruginosa-infected RAW264.7 cells. The results indicated that P. aeruginosa infection induced autophagy and apoptosis in RAW264.7 cells, and that rapamycin could suppress P. aeruginosa-induced apoptosis by regulating the expression of apoptosis-related proteins. In addition, rapamycin scavenged the cellular reactive oxygen species (ROS) and diminished p-JNK, p-ERK1/2 and p-p38 expression of MAPK pathways in RAW264.7 cells infected with P. aeruginosa. In conclusion, the promotion of autophagy decreased P. aeruginosa-induced ROS accumulation and further attenuated the apoptosis of RAW264.7 cells through MAPK pathway. These results provide novel insights into host–pathogen interactions and highlight a potential role of autophagy in eliminating P. aeruginosa.

HSP27 Protects Malignant Hematopoietic Cells Against VP-16-Induced Apoptosis through Modulation of P38 and C-JUN.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1276-1276
Author(s):  
Hein Schepers ◽  
Marjan Geugien ◽  
Marco van der Toorn ◽  
Anton L. Bryantsev ◽  
Harm H. Kampinga ◽  
...  
Keyword(s):  
Hematopoietic Cells ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Hsp27 Expression ◽  
Cd34 Cells ◽  
Induced Apoptosis ◽  
And Function ◽  
Jnk Activation

Abstract In the present study, expression and function of Heat Shock Protein 27 (HSP27) was analyzed in acute myeloid leukemia (AML), since HSP27 expression is linked to unfavourable prognosis. HSP27 protein was predominantly expressed in monocytic blasts (M4-M5, 91%, N = 11) and absent in myeloid leukemic blasts (M1-M2, N = 5). A similar lineage restricted expression was observed in normal hematopoietic cells: high expression in normal CD34+ cells and monocytes, and absent in granulocytes. To study the functional role of HSP27, RNA interference (RNAi) studies were performed in the leukemic TF-1 cell line. These experiments demonstrated a twofold increase in VP-16-induced apoptosis after HSP27 siRNA. In contrast, CD95 Fas-induced apoptosis remained the same, as a result of CD95 Fas-mediated upregulation of HSP27. Additional investigations demonstrated that the increased VP-16-induced apoptosis after HSP27 RNAi, was associated with an enhanced phosphorylation of p38 and c-Jun. This VP-16-induced phosphorylation was subsequently followed by the release of cytochrome c into the cytoplasm, which increased twofold after siRNA treatment. These results indicate that HSP27 plays an important role in the protection against VP-16-induced apoptosis through the modulation of p38 and JNK activation, probably through interference with DAXX-mediated ASK1 activation. This was further underscored by co-immunoprecipitation studies, demonstrating complex formation of DAXX and HSP27 in an ASK1-dependent manner. However, in the investigated AML samples, VP-16-mediated apoptosis correlated moderately with HSP27 expression, although HSP27 was highly expressed and phosphorylated and activated in primitive monocytic AML blasts. This is likely due to the co-expression of p21Waf1/Cip1, which is in the majority of the monocytic AML M4-M5 blasts constitutively localised in the cytoplasm and interferes with apoptosis via the DAXX-ASK1-dependent pathway. Preliminary data indicate that overexpression of a cytoplasmic form of p21 is able to reduce the VP-16-induced apoptosis after RNAi for HSP27 as compared to controls, suggesting a predominant anti-apoptotic role of p21 over HSP27. In summary, we demonstrate a role for HSP27 in the survival of leukemic cells by modulation of the DAXX/p38/JNK apoptosis pathway. This survival advantage can further be promoted by the co-expression of cytoplasmic localised p21Waf1/Cip1 protein, indicating that strategies in AML treatment should be focused on targeting multiple signal transduction pathways.

scholarly journals Lycium barbarumPolysaccharides Protect Rat Corneal Epithelial Cells against Ultraviolet B-Induced Apoptosis by Attenuating the Mitochondrial Pathway and Inhibiting JNK Phosphorylation

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Shaobo Du ◽  
Biao Han ◽  
Kang Li ◽  
Xuan Zhang ◽  
Xueli Sha ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Underlying Mechanism ◽  
Mitochondrial Pathway ◽  
Ultraviolet B ◽  
Lycium Barbarum ◽  
Apoptosis Pathway ◽  
Corneal Epithelial ◽  
Mitochondrial Apoptosis Pathway ◽  
Induced Apoptosis

Lycium barbarumpolysaccharides (LBPs) have been shown to play a key role in protecting the eyes by reducing the apoptosis induced by certain types of damage. However, it is not known whether LBPs can protect damaged corneal cells from apoptosis. Moreover, no reports have focused on the role of LBPs in guarding against ultraviolet B- (UVB-) induced apoptosis. The present study aimed to investigate the protective effect and underlying mechanism of LBPs against UVB-induced apoptosis in rat corneal epithelial (RCE) cells. The results showed that LBPs significantly prevented the loss of cell viability and inhibited cell apoptosis induced by UVB in RCE cells. LBPs also inhibited UVB-induced loss of mitochondrial membrane potential, downregulation ofBcl-2, and upregulation ofBaxand caspase-3. Finally, LBPs attenuated the phosphorylation of c-Jun NH2-terminal kinase (JNK) triggered by UVB. In summary, LBPs protect RCE cells against UVB-induced damage and apoptosis, and the underlying mechanism involves the attenuation of the mitochondrial apoptosis pathway and the inhibition of JNK phosphorylation.

scholarly journals Foreign RNA Induces the Degradation of Mitochondrial Antiviral Signaling Protein (MAVS): The Role of Intracellular Antiviral Factors

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e45136 ◽  
Author(s):  
Fei Xing ◽  
Tomoh Matsumiya ◽  
Koji Onomoto ◽  
Ryo Hayakari ◽  
Tadaatsu Imaizumi ◽  
...  
Keyword(s):  
Antiviral Signaling ◽  
Signaling Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

scholarly journals Contribution of glutaredoxin-1 to Fas s-glutathionylation in ethanol-induced liver injury

2020 ◽  
Author(s):  
Xiaomin Sun ◽  
Qin Deng ◽  
Yunfei Zhang ◽  
Jingyu Chen ◽  
chunbao guo
Keyword(s):  
Liver Injury ◽  
Alcohol Exposure ◽  
Nuclear Factor Κb ◽  
Signaling Cascades ◽  
Alcoholic Liver Injury ◽  
Genetic Ablation ◽  
Induced Apoptosis ◽  
The Impact ◽  
Deficient Mice

Abstract Background The reversible glutathionylation modification (PSSG) of Fas augments apoptosis, which can be reversed by the cytosolic deglutathionylation enzyme glutaredoxin-1 (Grx1), but its roles in alcoholic liver injury remain unknown. Therefore, the objective of this study was to investigate the impact of genetic ablation of Grx1 on Fas-SSG in regulating ethanol-induced injury. Methods The role of Grx1 in alcoholic liver injury was investigated in Grx1 knockout mice. Alcoholic liver injury was achieved by feeding mice with a liquid diet containing 5% ethanol for 2 weeks. Results We demonstrated that ethanol-fed mice had increased Grx1 activity and oxidative damage in the liver. On the other hand, Grx1-deficient mice had more serious liver damage when exposed to ethanol compared to that of wild-type mice, accompanied by increased alanine aminotransferase and aspartate aminotransferase levels, Fas-SSG, cleaved caspase-3 and hepatocyte apoptosis. Grx1 ablation resulted in the suppression of ethanol-induced nuclear factor-κB (NF-κB) signaling, its downstream signal, and Akt signaling cascades, which are required for protection against Fas-mediated apoptosis. Accordingly, blocking NK-κB prevented Fas-induced apoptosis in WT mice but not Grx1-/- mice. Furthermore, the number of Kupffer cells and related proinflammatory cytokines, including Akt, were lower in Grx1-/- livers than those of the controls. Conclusions Grx1 is essential for adaptation to alcohol exposure-induced oxidative injury by modulating Fas-SSG and Fas-induced apoptosis.

scholarly journals Exosome-mediated apoptosis pathway during WSSV infection in crustacean mud crab

2020 ◽  
Author(s):  
Yi Gong ◽  
Tongtong Kong ◽  
Xin Ren ◽  
Jiao Chen ◽  
Shanmeng Lin ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Dna Fragmentation ◽  
Protein Complex ◽  
Cellular Response ◽  
Mud Crab ◽  
Apoptosis Pathway ◽  
Exosomal Mirnas ◽  
Apoptosis Inducing Factor ◽  
Mitochondria Apoptosis Pathway

AbstractMicroRNAs are regulatory molecules that can be packaged into exosomes to modulate recipient’s cellular response, while their role during viral infection is beginning to be appreciated. However, the involvement of exosomal miRNAs during immunoregulation in invertebrates has not been addressed. Here, we found that exosomes released from WSSV-injected mud crabs could suppress viral invasion by inducing apoptosis of hemocytes. Besides, miR-137 and miR-7847 were found to be less packaged in mud crab exosomes during viral infection, with both miR-137 and miR-7847 shown to be negative apoptosis regulators by targeting the apoptosis-inducing factor (AIF). Moreover, our data revealed that AIF did not only translocate to the nucleus to induce DNA fragmentation, but could also competitively bind to HSP70 to disintegrate the HSP70-Bax (Bcl-2-associated X protein) complex, which eventually activated the mitochondria apoptosis pathway via free Bax. Therefore, our findings provides a novel mechanism underlying the crosstalk between exosomal miRNAs and apoptosis pathway in innate immunity in invertebrates.

scholarly journals Differential roles of RIG-I-like receptors in SARS-CoV-2 infection

2021 ◽  
Author(s):  
Duomeng Yang ◽  
Tingting Geng ◽  
Andrew G. Harrison ◽  
Penghua Wang
Keyword(s):  
Dominant Role ◽  
Type I ◽  
Wild Type ◽  
First Line ◽  
Rna Sensors ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein ◽  
Initial Target ◽  
Inducible Gene

AbstractThe retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) are the major viral RNA sensors that are essential for activation of antiviral immune responses. However, their roles in severe acute respiratory syndrome (SARS)-causing coronavirus (CoV) infection are largely unknown. Herein we investigate their functions in human epithelial cells, the primary and initial target of SARS-CoV-2, and the first line of host defense. A deficiency in MDA5 (MDA5−/−), RIG-I or mitochondrial antiviral signaling protein (MAVS) greatly enhanced viral replication. Expression of the type I/III interferons (IFN) was upregulated following infection in wild-type cells, while this upregulation was severely abolished in MDA5−/− and MAVS−/−, but not in RIG-I−/− cells. Of note, ACE2 expression was ~2.5 fold higher in RIG-I−/− than WT cells. These data demonstrate a dominant role of MDA5 in activating the type I/III IFN response to SARS-CoV-2, and an IFN-independent anti-SARS-CoV-2 role of RIG-I.

scholarly journals Differential roles of RIG-I like receptors in SARS-CoV-2 infection

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Duo-Meng Yang ◽  
Ting-Ting Geng ◽  
Andrew G. Harrison ◽  
Peng-Hua Wang
Keyword(s):  
Epithelial Cells ◽  
Mrna Level ◽  
Type I ◽  
Angiotensin Converting Enzyme 2 ◽  
Mitochondrial Antiviral Signaling ◽  
Entry Receptor ◽  
Mitochondrial Antiviral Signaling Protein ◽  
Initial Target ◽  
Inducible Gene

AbstractRetinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) sense viral RNA and activate antiviral immune responses. Herein we investigate their functions in human epithelial cells, the primary and initial target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A deficiency in MDA5, RIG-I or mitochondrial antiviral signaling protein (MAVS) enhanced viral replication. The expression of the type I/III interferon (IFN) during infection was impaired in MDA5−/− and MAVS−/−, but not in RIG-I−/−, when compared to wild type (WT) cells. The mRNA level of full-length angiotensin-converting enzyme 2 (ACE2), the cellular entry receptor for SARS-CoV-2, was ~ 2.5-fold higher in RIG-I−/− than WT cells. These data demonstrate MDA5 as the predominant SARS-CoV-2 sensor, IFN-independent induction of ACE2 and anti-SARS-CoV-2 role of RIG-I in epithelial cells.

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