ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy

Li, Zhihong; Zhang, Xinheng; Song, Cailiang; Lin, Wencheng; Cheng, Yuzhen; Xie, Zili; Chen, Sheng; Nie, Yu; Li, Aijun; Zhang, Huanmin; Li, Hongxin; Li, Haiyun; Xie, Qingmei

doi:10.1038/s41419-020-02841-y

Cited by 27 publications

(20 citation statements)

References 61 publications

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“…Increasing evidence has demonstrated that viruses can modulate the autophagic mechanism to escape degradation. For example, upon entry into host cells, certain viruses induce incomplete autophagy by enhancing lysosomal acidification or blocking the fusion of autophagosomes with lysosomes to escape lysosomal degradation ( Liao et al, 2020 ; Lin et al, 2020b ). Thus, we propose that RGNNV may employ a similar strategy to prevent autophagic degradation and promote viral replication in infected cells.…”

Section: Discussionmentioning

confidence: 99%

Capsid protein from red-spotted grouper nervous necrosis virus induces incomplete autophagy by inactivating the HSP90ab1-AKT-MTOR pathway

Zhang

Jia

et al. 2022

Zoological Research

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As a highly important fish virus, nervous necrosis virus (NNV) has caused severe economic losses to the aquaculture industry worldwide. Autophagy, an evolutionarily conserved intracellular degradation process, is involved in the pathogenesis of several viruses. Although NNV can induce autophagy to facilitate infection in grouper fish spleen cells, how it initiates and mediates autophagy pathways during the initial stage of infection is still unclear. Here, we found that red-spotted grouper NNV (RGNNV) induced autophagosome formation in two fish cell lines at 1.5 and 3 h post infection, indicating that autophagy is activated upon entry of RGNNV. Moreover, autophagic detection showed that RGNNV entry induced incomplete autophagy by impairing the fusion of autophagosomes with lysosomes. Further investigation revealed that binding of the RGNNV capsid protein (CP) to the Lateolabrax japonicus heat shock protein HSP90ab1 (LjHSP90ab1), a cell surface receptor of RGNNV, contributed to RGNNV invasion-induced autophagy. Finally, we found that CP blocked the interaction of L. japonicus protein kinase B (AKT) with LjHSP90ab1 by competitively binding the NM domain of LjHSP90ab1 to inhibit the AKT-mechanistic target of the rapamycin (MTOR) pathway. This study provides novel insight into the relationship between NNV receptors and autophagy, which may help clarify the pathogenesis of NNV.

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Section: Discussionmentioning

confidence: 99%

Capsid protein from red-spotted grouper nervous necrosis virus induces incomplete autophagy by inactivating the HSP90ab1-AKT-MTOR pathway

Zhang

Jia

et al. 2022

Zoological Research

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“…GADD45B is reported to bind and activate MTK1/MEKK4 kinase, which is an upstream activator of p38 ( Tsuchimochi et al, 2010 ; Liao et al, 2020 ). Here we also found that overexpression of GADD45B could facilitate phosphorylation of p38 under docetaxel treatment.…”

Section: Discussionmentioning

confidence: 99%

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer

Wang

Gao

et al. 2021

Front. Cell Dev. Biol.

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BackgroundChemoresistance is the major cause of death in advanced prostate cancer (PCa), especially in metastatic PCa (mPCa). However, the molecular mechanisms underlying the chemoresistance of PCa remain unclear. Understanding the reason behind the drug resistance would be helpful in developing new treatment approaches.MethodsThe Cancer Genome Atlas, Gene Expression Omnibus datasets, and clinical samples were used to examine the correlation between growth arrest and DNA damage-inducible 45 beta (GADD45B) with clinical characteristics and prognosis. Lentiviral transfection was used to construct GADD45B overexpression cell lines. Hypoxic incubator, low serum medium, or docetaxel was used to build environmental stress model or chemotherapy cell model. The MTS assay and colony formation assay were used to test cell viability. Apoptosis and cell cycle were detected by flow cytometry. The RNA and protein levels of related biomarkers were tested by Western blotting and quantitative polymerase chain reaction. Bioinformatics analysis after RNA sequencing was performed to identify the possible mechanism of how GADD45B regulates chemotherapy resistance.ResultsGADD45B was related to distant metastasis but not to Gleason score, prostate-specific antigen level, T stage, or lymph node metastasis and indicated a good prognosis. The level of GADD45B increased significantly in PCa cells that faced environmental stress. It was found that a high level of GADD45B significantly enhanced the chemosensitivity. Furthermore, high GADD45B promoted cell apoptosis via mitogen-activated protein kinase (MAPK) pathway.ConclusionGADD45B promoted chemosensitivity of prostate cancer through MAPK pathway. GADD45B could serve as a diagnostic biomarker and therapeutic target for mPCa or chemotherapy-resistant patients.

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“…ALV-J can induce apoptosis and inhibit autophagy to slow cell growth [ 50 – 52 ]. In this study, the overexpression of chTERT in LMH cells inhibited the apoptosis of ALV-J-infected cells and promoted autophagy, ultimately promoting cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Mutual regulation between chicken telomerase reverse transcriptase and the Wnt/β-catenin signalling pathway inhibits apoptosis and promotes the replication of ALV-J in LMH cells

Xiang

et al. 2021

Vet Res

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This study aimed to explore the mutual regulation between chicken telomerase reverse transcriptase (chTERT) and the Wnt/β-catenin signalling pathway and its effects on cell growth and avian leukosis virus subgroup J (ALV-J) replication in LMH cells. First, LMH cells stably overexpressing the chTERT gene (LMH-chTERT cells) and corresponding control cells (LMH-NC cells) were successfully constructed with a lentiviral vector expression system. The results showed that chTERT upregulated the expression of β-catenin, Cyclin D1, TCF4 and c-Myc. chTERT expression level and telomerase activity were increased when cells were treated with LiCl. When the cells were treated with ICG001 or IWP-2, the activity of the Wnt/β-catenin signalling pathway was significantly inhibited, and chTERT expression and telomerase activity were also inhibited. However, when the β-catenin gene was knocked down by small interfering RNA (siRNA), the changes in chTERT expression and telomerase activity were consistent with those in cells treated with ICG001 or IWP-2. These results indicated that chTERT and the Wnt/β-catenin signalling pathway can be mutually regulated. Subsequently, we found that chTERT not only shortened the cell cycle to promote proliferation but also inhibited apoptosis by downregulating the expression of Caspase 3, Caspase 9 and BAX; upregulating BCL-2 and BCL-X expression; and promoting autophagy. Moreover, chTERT significantly enhanced the migration ability of LMH cells, upregulated the protein and mRNA expression of ALV-J and increased the virus titre. ALV-J replication promoted chTERT expression and telomerase activity.

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ALV-J inhibits autophagy through the GADD45β/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy

Cited by 27 publications

References 61 publications

Capsid protein from red-spotted grouper nervous necrosis virus induces incomplete autophagy by inactivating the HSP90ab1-AKT-MTOR pathway

Capsid protein from red-spotted grouper nervous necrosis virus induces incomplete autophagy by inactivating the HSP90ab1-AKT-MTOR pathway

GADD45B Is a Potential Diagnostic and Therapeutic Target Gene in Chemotherapy-Resistant Prostate Cancer

Mutual regulation between chicken telomerase reverse transcriptase and the Wnt/β-catenin signalling pathway inhibits apoptosis and promotes the replication of ALV-J in LMH cells

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