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Xiulong Xu
Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, P. R. China

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Journal article
Published: 08 May 2021 in Cell Death & Disease
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The sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.

ACS Style

Sumei Li; Jingxiang Wang; Yurong Lu; Yuqing Zhao; Richard A. Prinz; Xiulong Xu. Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells. Cell Death & Disease 2021, 12, 1 -13.

AMA Style

Sumei Li, Jingxiang Wang, Yurong Lu, Yuqing Zhao, Richard A. Prinz, Xiulong Xu. Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells. Cell Death & Disease. 2021; 12 (5):1-13.

Chicago/Turabian Style

Sumei Li; Jingxiang Wang; Yurong Lu; Yuqing Zhao; Richard A. Prinz; Xiulong Xu. 2021. "Inhibition of the sonic hedgehog pathway activates TGF-β-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells." Cell Death & Disease 12, no. 5: 1-13.

Journal article
Published: 01 March 2021 in Journal of General Virology
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Canine distemper virus (CDV) is the aetiological agent that causes canine distemper (CD). Currently, no antiviral drugs have been approved for CD treatment. A77 1726 is the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide. It inhibits the activity of Janus kinases (JAKs) and dihydroorotate dehydrogenase (DHO-DHase), a rate-limiting enzyme in de novo pyrimidine nucleotide synthesis. A77 1726 also inhibits the activity of p70 S6 kinase (S6K1), a serine/threonine kinase that phosphorylates and activates carbamoyl-phosphate synthetase (CAD), a second rate-limiting enzyme in the de novo pathway of pyrimidine nucleotide synthesis. Our present study focuses on the ability of A77 1726 to inhibit CDV replication and its underlying mechanisms. Here we report that A77 1726 decreased the levels of the N and M proteins of CDV and lowered the virus titres in the conditioned media of CDV-infected Vero cells. CDV replication was not inhibited by Ruxolitinib (Rux), a JAK-specific inhibitor, but by brequinar sodium (BQR), a DHO-DHase-specific inhibitor, and PF-4708671, an S6K1-specific inhibitor. Addition of exogenous uridine, which restores intracellular pyrimidine nucleotide levels, blocked the antiviral activity of A77 1726, BQR and PF-4708671. A77 1726 and PF-4708671 inhibited the activity of S6K1 in CDV-infected Vero cells, as evidenced by the decreased levels of CAD and S6 phosphorylation. S6K1 knockdown suppressed CDV replication and enhanced the antiviral activity of A77 1726. These observations collectively suggest that the antiviral activity of A77 1726 against CDV is mediated by targeting pyrimidine nucleotide synthesis via inhibiting DHO-DHase activity and S6K1-mediated CAD activation.

ACS Style

Yao Li; Li Yi; Sipeng Cheng; Yongshan Wang; Jiongjiong Wang; Jing Sun; Quan Zhang; Xiulong Xu. Inhibition of canine distemper virus replication by blocking pyrimidine nucleotide synthesis with A77 1726, the active metabolite of the anti-inflammatory drug leflunomide. Journal of General Virology 2021, 102, 001534 .

AMA Style

Yao Li, Li Yi, Sipeng Cheng, Yongshan Wang, Jiongjiong Wang, Jing Sun, Quan Zhang, Xiulong Xu. Inhibition of canine distemper virus replication by blocking pyrimidine nucleotide synthesis with A77 1726, the active metabolite of the anti-inflammatory drug leflunomide. Journal of General Virology. 2021; 102 (3):001534.

Chicago/Turabian Style

Yao Li; Li Yi; Sipeng Cheng; Yongshan Wang; Jiongjiong Wang; Jing Sun; Quan Zhang; Xiulong Xu. 2021. "Inhibition of canine distemper virus replication by blocking pyrimidine nucleotide synthesis with A77 1726, the active metabolite of the anti-inflammatory drug leflunomide." Journal of General Virology 102, no. 3: 001534.

Journal article
Published: 22 January 2021 in Cancers
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The sonic hedgehog (Shh) pathway plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. We and others have reported earlier that this pathway is highly activated in thyroid cancer. However, its role in thyroid cancer stem cell (CSC) self-renewal and tumor development remains incompletely understood. B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and SRY-Box Transcription Factor 2 (SOX2) are two CSC-related transcription factors that have been implicated in promoting CSC self-renewal. The objective of our current investigation was to determine the role of the Shh pathway in regulating BMI1 and SOX2 expression in thyroid cancer and promoting thyroid tumor growth and development. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 reduced BMI1 and SOX2 expression in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines. The opposite results were obtained in cells overexpressing Gli1 or its downstream transcription factor Snail. The Shh pathway regulated SOX2 and BMI1 expression at a transcriptional and post-transcriptional level, respectively. GANT61 treatment suppressed the growth of SW1736 CSC-derived tumor xenografts but did not significantly inhibit the growth of tumors grown from bulk tumor cells. Clinicopathological analyses of thyroid tumor specimens by immunohistochemical (IHC) staining revealed that BMI1 and SOX2 were highly expressed in thyroid cancer and correlated with Gli1 expression. Our study provides evidence that activation of the Shh pathway leads to increased BMI1 and SOX2 expression in thyroid cancer and promotes thyroid CSC-driven tumor initiation. Targeting the Shh pathway may have therapeutic value for treating thyroid cancer and preventing recurrence.

ACS Style

Yurong Lu; Yiwen Zhu; Shihan Deng; Yuhuang Chen; Wei Li; Jing Sun; Xiulong Xu. Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)—Related Transcription Factors and CSC-Driven Thyroid Tumor Growth. Cancers 2021, 13, 418 .

AMA Style

Yurong Lu, Yiwen Zhu, Shihan Deng, Yuhuang Chen, Wei Li, Jing Sun, Xiulong Xu. Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)—Related Transcription Factors and CSC-Driven Thyroid Tumor Growth. Cancers. 2021; 13 (3):418.

Chicago/Turabian Style

Yurong Lu; Yiwen Zhu; Shihan Deng; Yuhuang Chen; Wei Li; Jing Sun; Xiulong Xu. 2021. "Targeting the Sonic Hedgehog Pathway to Suppress the Expression of the Cancer Stem Cell (CSC)—Related Transcription Factors and CSC-Driven Thyroid Tumor Growth." Cancers 13, no. 3: 418.

Journal article
Published: 09 January 2021 in Veterinary Microbiology
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Autophagy plays an important role in restricting the growth of invading intracellular microbes. Salmonella (S) Typhimurium, an intracellular pathogen that causes gastroenteritis and food poisoning in humans, evades autophagic detection by multiple mechanisms. There has been growing interest in developing autophagy inducers as novel antimicrobial agents for treating intracellular bacterial infections. We recently reported that A77 1726, the active metabolite of the anti-inflammatory drug leflunomide, induces autophagy by activating AMP-activated protein kinase (AMPK) and Unc-51 like autophagy activating kinase 1 (ULK1). Our present study aims to determine if A77 1726 was able to restrict intracellular Salmonella growth by inducing autophagy. We first confirmed the ability of A77 1726 to induce autophagy by activating the AMPK-ULK1 axis in uninfected RAW264.7 (a murine macrophage cell line) and HeLa cells (a human cervical carcinoma cell line). A77 1726 enhanced autophagy in S. Typhimurium-infected cells, as evidenced by increased levels of LC3 lipidation and increased numbers of autophagosomes and autolysosomes. Confocal microscopy revealed that A77 1726 induced xenophagy in macrophages, as evidenced by an increased number of LC3-coated bacteria in the cytoplasm. A77 1726 significantly decreased the number of intracellular S. Typhimurium in macrophages. Taken together, our study has demonstrated the ability of A77 1726 to restrict intracellular S. Typhimurium growth in vitro by enhancing xenophagy.

ACS Style

Jing Zhuang; Xiaoyue Ji; Yue Zhu; Wei Liu; Jing Sun; Xinan Jiao; Xiulong Xu. Restriction of intracellular Salmonella typhimurium growth by the small-molecule autophagy inducer A77 1726 through the activation of the AMPK-ULK1 axis. Veterinary Microbiology 2021, 254, 108982 .

AMA Style

Jing Zhuang, Xiaoyue Ji, Yue Zhu, Wei Liu, Jing Sun, Xinan Jiao, Xiulong Xu. Restriction of intracellular Salmonella typhimurium growth by the small-molecule autophagy inducer A77 1726 through the activation of the AMPK-ULK1 axis. Veterinary Microbiology. 2021; 254 ():108982.

Chicago/Turabian Style

Jing Zhuang; Xiaoyue Ji; Yue Zhu; Wei Liu; Jing Sun; Xinan Jiao; Xiulong Xu. 2021. "Restriction of intracellular Salmonella typhimurium growth by the small-molecule autophagy inducer A77 1726 through the activation of the AMPK-ULK1 axis." Veterinary Microbiology 254, no. : 108982.

Journal article
Published: 06 December 2020 in Viruses
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Avian influenza virus (AIV) emerged and has continued to re-emerge, continuously posing great threats to animal and human health. The detection of hemagglutination inhibition (HI) or virus neutralization antibodies (NA) is essential for assessing immune protection against AIV. However, the HI/NA-independent immune protection is constantly observed in vaccines' development against H7N9 subtype AIV and other subtypes in chickens and mammals, necessitating the analysis of the cellular immune response. Here, we established a multi-parameter flow cytometry to examine the innate and adaptive cellular immune responses in chickens after intranasal infection with low pathogenicity H7N9 AIV. This assay allowed us to comprehensively define chicken macrophages, dendritic cells, and their MHC-II expression, NK cells, γδ T cells, B cells, and distinct T cell subsets in steady state and during infection. We found that NK cells and KUL01+ cells significantly increased after H7N9 infection, especially in the lung, and the KUL01+ cells upregulated MHC-II and CD11c expression. Additionally, the percentages and numbers of γδ T cells and CD8 T cells significantly increased and exhibited an activated phenotype with significant upregulation of CD25 expression in the lung but not in the spleen and blood. Furthermore, B cells showed increased in the lung but decreased in the blood and spleen in terms of the percentages or/and numbers, suggesting these cells may be recruited from the periphery after H7N9 infection. Our study firstly disclosed that H7N9 infection induced local and systemic cellular immune responses in chickens, the natural host of AIV, and that the flow cytometric assay developed in this study is useful for analyzing the cellular immune responses to AIVs and other avian infectious diseases and defining the correlates of immune protection.

ACS Style

Xiaoli Hao; Shuai Li; Lina Chen; Maoli Dong; Jiongjiong Wang; Jiao Hu; Min Gu; Xiaoquan Wang; Shunlin Hu; Daxin Peng; Xiufan Liu; Shaobin Shang. Establishing a Multicolor Flow Cytometry to Characterize Cellular Immune Response in Chickens Following H7N9 Avian Influenza Virus Infection. Viruses 2020, 12, 1396 .

AMA Style

Xiaoli Hao, Shuai Li, Lina Chen, Maoli Dong, Jiongjiong Wang, Jiao Hu, Min Gu, Xiaoquan Wang, Shunlin Hu, Daxin Peng, Xiufan Liu, Shaobin Shang. Establishing a Multicolor Flow Cytometry to Characterize Cellular Immune Response in Chickens Following H7N9 Avian Influenza Virus Infection. Viruses. 2020; 12 (12):1396.

Chicago/Turabian Style

Xiaoli Hao; Shuai Li; Lina Chen; Maoli Dong; Jiongjiong Wang; Jiao Hu; Min Gu; Xiaoquan Wang; Shunlin Hu; Daxin Peng; Xiufan Liu; Shaobin Shang. 2020. "Establishing a Multicolor Flow Cytometry to Characterize Cellular Immune Response in Chickens Following H7N9 Avian Influenza Virus Infection." Viruses 12, no. 12: 1396.

Journal article
Published: 08 October 2020 in Viruses
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Janus kinase (JAK) inhibitors have been developed as novel immunomodulatory drugs and primarily used for treating rheumatoid arthritis and other inflammatory diseases. Recent studies have suggested that this category of anti-inflammatory drugs could be potentially useful for the control of inflammation “storms” in respiratory virus infections. In addition to their role in regulating immune cell functions, JAK1 and JAK2 have been recently identified as crucial cellular factors involved in influenza A virus (IAV) replication and could be potentially targeted for antiviral therapy. Gingerenone A (Gin A) is a compound derived from ginger roots and a dual inhibitor of JAK2 and p70 S6 kinase (S6K1). Our present study aimed to determine the antiviral activity of Gin A on influenza A virus (IAV) and to understand its mechanisms of action. Here, we reported that Gin A suppressed the replication of three IAV subtypes (H1N1, H5N1, H9N2) in four cell lines. IAV replication was also inhibited by Ruxolitinib (Rux), a JAK inhibitor, but not by PF-4708671, an S6K1 inhibitor. JAK2 overexpression enhanced H5N1 virus replication and attenuated Gin A-mediated antiviral activity. In vivo experiments revealed that Gin A treatment suppressed IAV replication in the lungs of H5N1 virus-infected mice, alleviated their body weight loss, and prolonged their survival. Our study suggests that Gin A restricts IAV replication by inhibiting JAK2 activity; Gin A could be potentially useful for the control of influenza virus infections.

ACS Style

Jiongjiong Wang; Richard A. Prinz; Xiufan Liu; Xiulong Xu. In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2. Viruses 2020, 12, 1141 .

AMA Style

Jiongjiong Wang, Richard A. Prinz, Xiufan Liu, Xiulong Xu. In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2. Viruses. 2020; 12 (10):1141.

Chicago/Turabian Style

Jiongjiong Wang; Richard A. Prinz; Xiufan Liu; Xiulong Xu. 2020. "In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2." Viruses 12, no. 10: 1141.

Journal article
Published: 28 September 2020 in Marine Drugs
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Astaxanthin (AST) is a carotenoid with therapeutic values on hyperglycemia and diabetic complications. The mechanisms of action of AST remain incompletely understood. p70 S6 kinase 1 (S6K1) is a serine/threonine kinase that phosphorylates insulin receptor substrate 1 (IRS-1)S1101 and desensitizes the insulin receptor (IR). Our present study aims to determine if AST improves glucose metabolisms by targeting S6K1. Western blot analysis revealed that AST inhibited the phosphorylation of two S6K1 substrates, S6S235/236 and IRS-1S1101, but enhanced the phosphorylation of AKTT308, AKTS473, and S6K1T389 by feedback activation of the phosphatidylinositol-3 (PI-3) kinase in 3T3-L1 adipocytes and L6 myotubes. In vitro kinase assays revealed that AST inhibited S6K1 activity with an IC50 value of approximately 13.8 μM. AST increased insulin-induced IR tyrosine phosphorylation and IRS-1 binding to the p85 subunit of PI-3 kinase. Confocal microscopy revealed that AST increased the translocation of the glucose transporter 4 (GLUT4) to the plasma membrane in L6 cells. Glucose uptake assays using a fluorescent dye, 2-NBDG (2-N-(Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose), revealed that AST increased glucose uptake in 3T3-L1 adipocytes and L6 myotubes under insulin resistance conditions. Our study identifies S6K1 as a previously unrecognized molecular target of AST and provides novel insights into the mechanisms of action of AST on IR sensitization.

ACS Style

Chunmei Li; Bixia Ma; Junhong Chen; Yoonhwa Jeong; Xiulong Xu. Astaxanthin Inhibits p70 S6 Kinase 1 Activity to Sensitize Insulin Signaling. Marine Drugs 2020, 18, 495 .

AMA Style

Chunmei Li, Bixia Ma, Junhong Chen, Yoonhwa Jeong, Xiulong Xu. Astaxanthin Inhibits p70 S6 Kinase 1 Activity to Sensitize Insulin Signaling. Marine Drugs. 2020; 18 (10):495.

Chicago/Turabian Style

Chunmei Li; Bixia Ma; Junhong Chen; Yoonhwa Jeong; Xiulong Xu. 2020. "Astaxanthin Inhibits p70 S6 Kinase 1 Activity to Sensitize Insulin Signaling." Marine Drugs 18, no. 10: 495.

Research article
Published: 29 June 2020 in The FASEB Journal
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The newly reassorted IAV subtypes from zoonotic reservoirs respond poorly to current vaccines and antiviral therapy. There is an unmet need in developing novel antiviral drugs for better control of IAV infection. The cellular factors that are crucial for virus replication have been sought as novel molecular targets for antiviral therapy. Recent studies have shown that Janus kinases (JAK), JAK1, and JAK2, play an important role in IAV replication. Leflunomide is an anti‐inflammatory drug primarily used for treating rheumatoid arthritis (RA). Prior studies suggest that A77 1726, the active metabolite of leflunomide, inhibits the activity of JAK1 and JAK3. Our current study aims to determine if A77 1726 can function as a JAK inhibitor to control IAV infection. Here, we report that A77 1726 inhibited the replication of three IAV subtypes(H5N1, H1N1, H9N2)in three cell types (chicken embryonic fibroblasts, A549, and MDCK). A77 1726 inhibited JAK1, JAK2, and STAT3 tyrosine phosphorylation. Similar observations were made with Ruxolitinib (Rux), a JAK‐specific inhibitor. JAK2 overexpression enhanced H5N1 virus replication and compromised the antiviral activity of A77 1726. Leflunomide inhibited virus replication in the lungs of IAV‐infected mice, alleviated their body weight loss, and prolonged their survival. Our study demonstrates for the first time the ability of A77 1726 to inhibit JAK2 activity and suggests that inhibition of JAK activity contributes to its antiviral activity.

ACS Style

Jiongjiong Wang; Jing Sun; Jiao Hu; Chengming Wang; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. A77 1726, the active metabolite of the anti‐rheumatoid arthritis drug leflunomide, inhibits influenza A virus replication in vitro and in vivo by inhibiting the activity of Janus kinases. The FASEB Journal 2020, 34, 10132 -10145.

AMA Style

Jiongjiong Wang, Jing Sun, Jiao Hu, Chengming Wang, Richard A. Prinz, Daxin Peng, Xiufan Liu, Xiulong Xu. A77 1726, the active metabolite of the anti‐rheumatoid arthritis drug leflunomide, inhibits influenza A virus replication in vitro and in vivo by inhibiting the activity of Janus kinases. The FASEB Journal. 2020; 34 (8):10132-10145.

Chicago/Turabian Style

Jiongjiong Wang; Jing Sun; Jiao Hu; Chengming Wang; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. 2020. "A77 1726, the active metabolite of the anti‐rheumatoid arthritis drug leflunomide, inhibits influenza A virus replication in vitro and in vivo by inhibiting the activity of Janus kinases." The FASEB Journal 34, no. 8: 10132-10145.

Journal article
Published: 18 June 2020 in Virology
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Porcine epidemic diarrhea (PED) virus (PEDV) is a coronavirus that primarily infects porcine intestinal epithelial cells and causes severe diarrhea and high fatality in piglets. A77 1726 is the active metabolite of leflunomide, a clinically approved anti-rheumatoid arthritis (RA) drug. A77 1726 inhibits the activity of protein tyrosine kinases (PTKs), p70 S6 kinase (S6K1), and dihydroorotate dehydrogenase (DHO-DHase). Whether A77 1726 can control coronavirus infections has not been investigated. Here we report that A77 1726 effectively restricted PEDV replication by inhibiting Janus kinases (JAKs) and Src kinase activities but not by inhibiting DHO-DHase and S6K1 activities. Overexpression of Src, JAK2 or its substrate STAT3 enhanced PEDV replication and attenuated the antiviral activity of A77 1726. Our study demonstrates for the first time the ability of A77 1726 to control coronavirus replication by inhibiting PTK activities. Leflunomide has potential therapeutic value for the control of PEDV and other coronavirus infections.

ACS Style

Xiaomei Li; Jing Sun; Richard A. Prinz; Xiufan Liu; Xiulong Xu. Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases. Virology 2020, 551, 75 -83.

AMA Style

Xiaomei Li, Jing Sun, Richard A. Prinz, Xiufan Liu, Xiulong Xu. Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases. Virology. 2020; 551 ():75-83.

Chicago/Turabian Style

Xiaomei Li; Jing Sun; Richard A. Prinz; Xiufan Liu; Xiulong Xu. 2020. "Inhibition of porcine epidemic diarrhea virus (PEDV) replication by A77 1726 through targeting JAK and Src tyrosine kinases." Virology 551, no. : 75-83.

Journal article
Published: 01 June 2020 in Cell Reports
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Influenza A virus (IAV) primarily infects the airway and alveolar epithelial cells and disrupts the intercellular junctions, leading to increased paracellular permeability. Although this pathological change plays a critical role in lung tissue injury and secondary infection, the molecular mechanism of IAV-induced damage to the alveolar barrier remains obscure. Here, we report that Gli1, a transcription factor in the sonic hedgehog (Shh) signaling pathway, is cross-activated by the MAP and PI3 kinase pathways in H1N1 virus (PR8)-infected A549 cells and in the lungs of H1N1 virus-infected mice. Gli1 activation induces Snail expression, which downregulates the expression of intercellular junction proteins, including E-cadherin, ZO-1, and Occludin, and increases paracellular permeability. Inhibition of the Shh pathway restores the levels of Snail and intercellular junction proteins in H1N1-infected cells. Our study suggests that Gli1 activation plays an important role in disrupting the intercellular junctions and in promoting the pathogenesis of H1N1 virus infections.

ACS Style

Tao Ruan; Jing Sun; Wei Liu; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells. Cell Reports 2020, 31, 107801 .

AMA Style

Tao Ruan, Jing Sun, Wei Liu, Richard A. Prinz, Daxin Peng, Xiufan Liu, Xiulong Xu. H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells. Cell Reports. 2020; 31 (13):107801.

Chicago/Turabian Style

Tao Ruan; Jing Sun; Wei Liu; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. 2020. "H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells." Cell Reports 31, no. 13: 107801.

Research article
Published: 23 April 2020 in Cellular Microbiology
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Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that damages gastrointestinal tissue and causes severe diarrhea. The mechanisms by which Salmonella disrupts epithelial barrier and increases the paracellular permeability are incompletely understood. Our present study aims to determine the role of Gli1, a transcription factor activated in the sonic hedgehog (Shh) pathway, in decreasing the levels of apical junction proteins in a Salmonella‐infected human colonic epithelial cancer cell line, Caco‐2, and in the intestinal tissue of Salmonella‐infected mice. Here we report that S. Typhimurium increased the mRNA and protein levels of Gli1 and Snail, a downstream transcription factor that plays an important role in the epithelial‐to‐mesenchymal transition (EMT). S. Typhimurium also decreased the levels of E‐cadherin and three tight junction proteins (ZO‐1, claudin‐1, and occludin). Gli1 siRNA and GANT61, a Gli1‐specific inhibitor, blocked S. Typhimurium‐induced Snail expression, restored the levels of E‐cadherin and tight junction proteins, and prevented S. Typhimurium‐increased paracellular permeability. Further study showed that Gli1 was cross‐activated by the MAP and PI‐3 kinase pathways. S. Typhimurium devoid of sopB, an effector of the Type 3 secretion system (T3SS) responsible for AKT activation, was unable to induce Snail expression and to decrease the expression of apical junction proteins. Our study uncovered a novel role of Gli1 in mediating the Salmonella‐induced disruption of the intestinal epithelial barrier. This article is protected by copyright. All rights reserved.

ACS Style

Wei Liu; Tao Ruan; Xiaoyue Ji; Di Ran; Jing Sun; Huoying Shi; Richard A. Prinz; Jun Sun; Zhiming Pan; Xinan Jiao; Xiulong Xu. The Gli1‐Snail axis contributes to Salmonella Typhimurium‐induced disruption of intercellular junctions of intestinal epithelial cells. Cellular Microbiology 2020, 22, 1 .

AMA Style

Wei Liu, Tao Ruan, Xiaoyue Ji, Di Ran, Jing Sun, Huoying Shi, Richard A. Prinz, Jun Sun, Zhiming Pan, Xinan Jiao, Xiulong Xu. The Gli1‐Snail axis contributes to Salmonella Typhimurium‐induced disruption of intercellular junctions of intestinal epithelial cells. Cellular Microbiology. 2020; 22 (8):1.

Chicago/Turabian Style

Wei Liu; Tao Ruan; Xiaoyue Ji; Di Ran; Jing Sun; Huoying Shi; Richard A. Prinz; Jun Sun; Zhiming Pan; Xinan Jiao; Xiulong Xu. 2020. "The Gli1‐Snail axis contributes to Salmonella Typhimurium‐induced disruption of intercellular junctions of intestinal epithelial cells." Cellular Microbiology 22, no. 8: 1.

Preprint content
Published: 14 January 2020
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Autophagy is a cellular process to clear pathogens. Salmonella enterica serovar Enteritidis (S.E) has emerged as one of the most important food-borne pathogens. However, major studies still focus on Salmonella enterica serovar Typhimurium. Here, we reported that AvrA, a S. Enteritidis effector, inhibited autophagy to promote bacterial survival in the host. We found that AvrA regulates the conversion of LC3 I into LC3 II and the enrichment of lysosomes. Beclin-1, a key molecular regulator of autophagy, was decreased after AvrA expressed strain colonization. In S.E-AvrA--infected cells, we found the increases of protein levels of p-JNK and p-c-Jun and the transcription level of AP-1. AvrA-reduction of Beclin-1 protein expression is through the JNK pathway. The JNK inhibitor abolished the AvrA-reduced Beclin-1 protein expression. Moreover, we identified that the AvrA mutation C186A abolished its regulation of Beclin-1 expression. In addition, AvrA protein interacted with Beclin-1. In organoids and infected mice, we explored the physiologically related effects and mechanism of AvrA in reducing Beclin-1 through the JNK pathway, thus attenuating autophagic responses.ImportanceSalmonella Enteritidis is an important pathogen with a public health concern and farm production risk, yet the host-pathogen interactions that govern the survival of S. Enteritidis infections are incompletely understood. Anti-bacterial autophagy provides potent cell-autonomous immunity against bacterial colonization. Here, we report that a new role for effector AvrA of S. Enteritidis in the reduction of Beclin-1 protein expression through the JNK pathway and the attenuation of the autophagic response in intestinal epithelial cells. This finding not only indicates an important role of S. Enteritidis effector in reducing host protein as a strategy to suppress autophagy, but also suggests manipulating autophagy as a new strategy to treat infectious diseases.

ACS Style

Yang Jiao; Yong-Guo Zhang; Zhijie Lin; Rong Lu; Yinglin Xia; Chuang Meng; Zhiming Pan; Xiulong Xu; Xin-An Jiao; Jun Sun. Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein. 2020, 1 .

AMA Style

Yang Jiao, Yong-Guo Zhang, Zhijie Lin, Rong Lu, Yinglin Xia, Chuang Meng, Zhiming Pan, Xiulong Xu, Xin-An Jiao, Jun Sun. Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein. . 2020; ():1.

Chicago/Turabian Style

Yang Jiao; Yong-Guo Zhang; Zhijie Lin; Rong Lu; Yinglin Xia; Chuang Meng; Zhiming Pan; Xiulong Xu; Xin-An Jiao; Jun Sun. 2020. "Salmonella Enteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein." , no. : 1.

Journal article
Published: 10 September 2019 in Virology
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Activation of c-Jun terminal kinase (JNK) by the nonstructural protein 1 (NS1) of the H5N1 subtype of influenza A virus (IAV) plays an important role in inducing autophagy and virus replication. However, the mechanisms of NS1-induced JNK activation remain elusive. Here we first confirmed the ability of H5N1 (A/mallard/Huadong/S/2005) to activate JNK and to induce autophagy in 293T cells, a human embryonic kidney cell line. We further showed that TAK1, MAP kinase kinase 4 (MKK4), and JNK were activated in 293T cells transfected with the NS1 gene of the H5N1 virus. JNK activation by the NS1 protein or by H5N1 virus was blocked by 5Z-7-Oxozeaenol (5Z), a TAK1-specific inhibitor, and by TAK1 siRNA. Further study showed that 5Z and TAK1 siRNA suppressed H5N1 virus-induced autophagy and inhibited virus replication. Our study unveiled a previously unrecognized role of TAK1 in IAV replication, IAV-induced JNK activation, and autophagy.

ACS Style

Tianyu Sheng; Yuling Sun; Jing Sun; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. Role of TGF-β-activated kinase 1 (TAK1) activation in H5N1 influenza A virus-induced c-Jun terminal kinase activation and virus replication. Virology 2019, 537, 263 -271.

AMA Style

Tianyu Sheng, Yuling Sun, Jing Sun, Richard A. Prinz, Daxin Peng, Xiufan Liu, Xiulong Xu. Role of TGF-β-activated kinase 1 (TAK1) activation in H5N1 influenza A virus-induced c-Jun terminal kinase activation and virus replication. Virology. 2019; 537 ():263-271.

Chicago/Turabian Style

Tianyu Sheng; Yuling Sun; Jing Sun; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. 2019. "Role of TGF-β-activated kinase 1 (TAK1) activation in H5N1 influenza A virus-induced c-Jun terminal kinase activation and virus replication." Virology 537, no. : 263-271.

Journal article
Published: 26 August 2019 in Cellular Microbiology
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It has been long recognised that activation of toll-like receptors (TLRs) induces autophagy to restrict intracellular bacterial growth. However, the mechanisms of TLR-induced autophagy are incompletely understood. Salmonella Typhimurium is an intracellular pathogen that causes food poisoning and gastroenteritis in humans. Whether TLR activation contributes to S. Typhimurium-induced autophagy has not been investigated. Here, we report that S. Typhimurium and TLRs shared a common pathway to induce autophagy in macrophages. We first showed that S. Typhimurium-induced autophagy in a RAW264.7 murine macrophage cell line was mediated by the AMP-activated protein kinase (AMPK) through activation of the TGF-β-activated kinase (TAK1), a kinase activated by multiple TLRs. AMPK activation led to increased phosphorylation of Unc-51-like autophagy activating kinase (ULK1) at S317 and S555. ULK1 phosphorylation at these two sites in S. Typhimurium-infected macrophages overrode the inhibitory effect of mTOR on ULK1 activity due to mTOR-mediated ULK1 phosphorylation at S757. Lipopolysaccharide (LPS), flagellin, and CpG oligodeoxynucleotide, which activate TLR4, TLR5, and TLR9, respectively, increased TAK1 and AMPK phosphorylation and induced autophagy in RAW264.7 cells and in bone marrow-derived macrophages. However, LPS was unable to induce TAK1 and AMPK phosphorylation and autophagy in TLR4-deficient macrophages. TAK1 and AMPK-specific inhibitors blocked S. Typhimurium-induced autophagy and xenophagy and increased the bacterial growth in RAW264.7 cells. These observations collectively suggest that activation of the TAK1-AMPK axis through TLRs is essential for S. Typhimurium-induced autophagy and that TLR signalling cross-activates the autophagic pathway to clear intracellular bacteria.

ACS Style

Wei Liu; Jing Zhuang; Yuanyuan Jiang; Jing Sun; Richard A. Prinz; Jun Sun; Xinan Jiao; Xiulong Xu. Toll‐like receptor signalling cross‐activates the autophagic pathway to restrictSalmonellaTyphimurium growth in macrophages. Cellular Microbiology 2019, 21, e13095 .

AMA Style

Wei Liu, Jing Zhuang, Yuanyuan Jiang, Jing Sun, Richard A. Prinz, Jun Sun, Xinan Jiao, Xiulong Xu. Toll‐like receptor signalling cross‐activates the autophagic pathway to restrictSalmonellaTyphimurium growth in macrophages. Cellular Microbiology. 2019; 21 (12):e13095.

Chicago/Turabian Style

Wei Liu; Jing Zhuang; Yuanyuan Jiang; Jing Sun; Richard A. Prinz; Jun Sun; Xinan Jiao; Xiulong Xu. 2019. "Toll‐like receptor signalling cross‐activates the autophagic pathway to restrictSalmonellaTyphimurium growth in macrophages." Cellular Microbiology 21, no. 12: e13095.

Research article
Published: 17 October 2018 in Molecular Nutrition & Food Research
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Scope The bioactive constituents in ginger extract responsible for their anti‐hyperglycemic effect and the underlying mechanisms are incompletely understood. Gingerenone A (Gin A) has been identified as an inhibitor of p70 S6 (S6K1), a kinase that plays a critical role in the pathogenesis of insulin resistance. Our study aims to evaluate if Gin A can sensitizes the insulin receptor by inhibiting S6K1 activity. Methods and results Western blot analysis revealed that Gin A induced phosphatidylinositide‐3 kinase (PI3K) feedback activation in murine 3T3‐L1 adipocytes and rat L6 myotubes, as evidenced by increased AKTS473 and S6K1T389 but decreased S6S235/236 and insulin receptor substrate 1 (IRS‐1)S1101 phosphorylation. Western blot and immunoprecipitation analysis revealed that Gin A increased insulin receptor tyrosine phosphorylation in L6 myotubes and IRS‐1 binding to the PI3K in 3T3‐L1 adipocytes. Confocal microscopy revealed that Gin A enhanced insulin‐induced translocation of glucose transporter 4 (GLUT4) into the cell membrane in L6 cells. 2‐NBDG (2‐N‐(Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl)amino) ‐2‐deoxyglucose) fluorescent assay revealed that Gin A enhanced insulin‐stimulated glucose uptake in 3T3‐L1 adipocytes and L6 myotubes. Conclusions Gin A overcomes insulin resistance and increases glucose uptake by inhibiting S6K1 activity. Gin A or other plant‐derived S6K1 inhibitors could be developed as novel anti‐diabetic agents. This article is protected by copyright. All rights reserved

ACS Style

Junhong Chen; Jing Sun; Richard A. Prinz; Yi Li; Xiulong Xu. Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase. Molecular Nutrition & Food Research 2018, 62, e1800709 .

AMA Style

Junhong Chen, Jing Sun, Richard A. Prinz, Yi Li, Xiulong Xu. Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase. Molecular Nutrition & Food Research. 2018; 62 (23):e1800709.

Chicago/Turabian Style

Junhong Chen; Jing Sun; Richard A. Prinz; Yi Li; Xiulong Xu. 2018. "Gingerenone A Sensitizes the Insulin Receptor and Increases Glucose Uptake by Inhibiting the Activity of p70 S6 Kinase." Molecular Nutrition & Food Research 62, no. 23: e1800709.

Comparative study
Published: 10 October 2018 in Virology
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The non-structural protein 1 (NS1) of different influenza A virus (IAV) strains can differentially regulate the activity of c-Jun terminal kinase (JNK) and PI-3 kinase (PI3K). Whether varying JNK and PI3K activation impacts autophagy and IAV replication differently remains uncertain. Here we report that H5N1 (A/mallard/Huadong/S/2005) influenza A virus induced functional autophagy, as evidenced by increased LC3 lipidation and decreased p62 levels, and the presence of autolysosomes in chicken fibroblast cells. H9N2 (A/chicken/Shanghai/F/98) virus weakly induced autophagy, whereas H1N1 virus (A/PR/8/34, PR8) blocked autophagic flux. H5N1 virus activated JNK but inhibited the PI-3 kinase pathway. In contrast, N9N2 virus infection led to modest JNK activation and strong PI-3 kinase activation; whereas H1N1 virus activated the PI-3 kinase pathway but did not activate JNK. SP600125, a JNK inhibitor, inhibited H5N1 virus-induced autophagy and virus replication in a DF-1 chicken fibroblast cell line. Our study uncovered a previously unrecognized role of JNK in IAV replication and autophagy.

ACS Style

Jingting Zhang; Tao Ruan; Tianyu Sheng; Jiongjiong Wang; Jing Sun; Jin Wang; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. Role of c-Jun terminal kinase (JNK) activation in influenza A virus-induced autophagy and replication. Virology 2018, 526, 1 -12.

AMA Style

Jingting Zhang, Tao Ruan, Tianyu Sheng, Jiongjiong Wang, Jing Sun, Jin Wang, Richard A. Prinz, Daxin Peng, Xiufan Liu, Xiulong Xu. Role of c-Jun terminal kinase (JNK) activation in influenza A virus-induced autophagy and replication. Virology. 2018; 526 ():1-12.

Chicago/Turabian Style

Jingting Zhang; Tao Ruan; Tianyu Sheng; Jiongjiong Wang; Jing Sun; Jin Wang; Richard A. Prinz; Daxin Peng; Xiufan Liu; Xiulong Xu. 2018. "Role of c-Jun terminal kinase (JNK) activation in influenza A virus-induced autophagy and replication." Virology 526, no. : 1-12.

Journal article
Published: 11 May 2018 in Cell Death & Disease
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Autophagy is a conserved cellular process that functions as a first-line defense to restrict the growth of invading parasitic bacteria. As an intracellular pathogen, Salmonella (S) Typhimurium invades host cells through two Type III secretion systems (T3SS) and resides in the Salmonella-containing vacuole (SCV). When the SCV membrane is perforated and ruptured by T3SS-1, a small portion of the Salmonella egresses from the SCV and replicates rapidly in the nutrient-rich cytosol. Cytosolic Salmonella and those residing in the membrane-damaged SCV are tagged by ubiquitination and marked for autophagy through the ubiquitin-binding adaptor proteins such as p62, NDP52, and optineurin. Prior studies suggest that transient intracellular amino-acid starvation and subsequent inactivation of the mechanistic target of rapamycin (mTOR), a key molecule that phosphorylates Unc-51 like autophagy activating kinase (ULK1) and inhibits its activity, can trigger autophagy in S. Typhimurium-infected cells. Other studies suggest that energy stress in S. Typhimurium-infected cells leads to AMP-activated protein kinase (AMPK) activation and autophagy. In the present study, we report that autophagy was rapidly induced in S. Typhimurium-infected cells, as evidenced by increased LC3 lipidation and decreased p62 levels. However, S. Typhimurium infection drastically increased AKT phosphorylation but decreased S6K1T389, 4E-BPT37/46, and ULK1S757 phosphorylation, suggesting that mTOR activation by AKT is subverted. Further studies showed that AMPK was activated in S. Typhimurium-infected cells, as evidenced by increased ULK1S317 and ACCS79 phosphorylation. AMPK activation was mediated by Toll-like receptor-activated TAK1. Functional studies revealed that AMPK and TAK1 inhibitors accelerated S. Typhimurium growth in HeLa cells. Our results strongly suggest that TAK1 activation leads to AMPK activation, which activates ULK1 by phosphorylating ULK1S317 and suppressing mTOR activity and ULK1S757 phosphorylation. Our study has unveiled a previously unrecognized pathway for S. Typhimurium-induced autophagy.

ACS Style

Wei Liu; Yuanyuan Jiang; Jing Sun; Shizhong Geng; Zhiming Pan; Richard A. Prinz; Chengming Wang; Jun Sun; Xinan Jiao; Xiulong Xu. Activation of TGF-β-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy. Cell Death & Disease 2018, 9, 1 -16.

AMA Style

Wei Liu, Yuanyuan Jiang, Jing Sun, Shizhong Geng, Zhiming Pan, Richard A. Prinz, Chengming Wang, Jun Sun, Xinan Jiao, Xiulong Xu. Activation of TGF-β-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy. Cell Death & Disease. 2018; 9 (5):1-16.

Chicago/Turabian Style

Wei Liu; Yuanyuan Jiang; Jing Sun; Shizhong Geng; Zhiming Pan; Richard A. Prinz; Chengming Wang; Jun Sun; Xinan Jiao; Xiulong Xu. 2018. "Activation of TGF-β-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy." Cell Death & Disease 9, no. 5: 1-16.

Journal article
Published: 01 April 2018 in Journal of Endocrinology
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P70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKTS473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS-1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in ob/ob and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKTS473/T308 phosphorylation in the fat and muscle of ob/ob mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity in vitro, and that leflunomide could be potentially useful for treating patients with both RA and diabetes.

ACS Style

Junhong Chen; Jing Sun; Michelle E Doscas; Jin Ye; Ashley J Williamson; Yanchun Li; Yi Li; Richard A Prinz; Xiulong Xu. Control of hyperglycemia in male mice by leflunomide: mechanisms of action. Journal of Endocrinology 2018, 237, 43 -58.

AMA Style

Junhong Chen, Jing Sun, Michelle E Doscas, Jin Ye, Ashley J Williamson, Yanchun Li, Yi Li, Richard A Prinz, Xiulong Xu. Control of hyperglycemia in male mice by leflunomide: mechanisms of action. Journal of Endocrinology. 2018; 237 (1):43-58.

Chicago/Turabian Style

Junhong Chen; Jing Sun; Michelle E Doscas; Jin Ye; Ashley J Williamson; Yanchun Li; Yi Li; Richard A Prinz; Xiulong Xu. 2018. "Control of hyperglycemia in male mice by leflunomide: mechanisms of action." Journal of Endocrinology 237, no. 1: 43-58.

Journal article
Published: 14 March 2018 in Cell Death & Disease
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Autophagy plays a central role in degrading misfolded proteins such as mutated superoxide dismutase 1 (SOD1), which forms aggregates in motor neurons and is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Autophagy is activated when UNC-51-like kinase 1 (ULK1) is phosphorylated at S555 and activated by AMP-activated protein kinase (AMPK). Autophagy is suppressed when ULK1 is phosphorylated at S757 by the mechanistic target of rapamycin (mTOR). Whether p70 S6 kinase 1 (S6K1), a serine/threonine kinase downstream of mTOR, can also regulate autophagy remains uncertain. Here we report that inhibition of S6K1 by A77 1726, the active metabolite of an anti-inflammatory drug leflunomide, induced mTOR feedback activation and ULK1S757 phosphorylation in NSC34 cells, a hybrid mouse motoneuron cell line. Unexpectedly, A77 1726 did not suppress but rather induced autophagy by increasing AMPKT172 and ULK1S555 phosphorylation. Similar observations were made with PF-4708671, a specific S6K1 inhibitor, or with S6K1 siRNA. Further studies showed that A77 1726 induced AMPK phosphorylation by activating the TGF-β-activated kinase 1 (TAK1). Functional studies revealed that A77 1726 induced co-localization of mutant SOD1G93A protein aggregates with autophagosomes and accelerated SOD1G93A protein degradation, which was blocked by inhibition of autophagy through autophagy-related protein 7 (ATG7) siRNA. Our study suggests that S6K1 inhibition induces autophagy through TAK1-mediated AMPK activation in NSC34 cells, and that blocking S6K1 activity by a small molecule inhibitor such as leflunomide may offer a new strategy for ALS treatment.

ACS Style

Jing Sun; Yarong Mu; Yuanyuan Jiang; Ruilong Song; Jianxin Yi; Jingsong Zhou; Jun Sun; Xinan Jiao; Richard A. Prinz; Yi Li; Xiulong Xu. Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates. Cell Death & Disease 2018, 9, 407 .

AMA Style

Jing Sun, Yarong Mu, Yuanyuan Jiang, Ruilong Song, Jianxin Yi, Jingsong Zhou, Jun Sun, Xinan Jiao, Richard A. Prinz, Yi Li, Xiulong Xu. Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates. Cell Death & Disease. 2018; 9 (3):407.

Chicago/Turabian Style

Jing Sun; Yarong Mu; Yuanyuan Jiang; Ruilong Song; Jianxin Yi; Jingsong Zhou; Jun Sun; Xinan Jiao; Richard A. Prinz; Yi Li; Xiulong Xu. 2018. "Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates." Cell Death & Disease 9, no. 3: 407.

Original article
Published: 06 January 2018 in Archives of Virology
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During surveillance for avian influenza viruses, three H5N6 viruses were isolated in chickens obtained from live bird markets in eastern China, between January 2015 and April 2016. Sequence analysis revealed a high genomic homology between these poultry isolates and recent human H5N6 variants whose internal genes were derived from genotype S H9N2 avian influenza viruses. Glycan binding assays revealed that all avian H5N6 viruses were capable of binding to both human-type SAα-2,6Gal receptors and avian-type SAα-2,3Gal receptors. Their biological characteristics were further studied in BALB/c mice, specific-pathogen-free chickens, and mallard ducks. All three isolates had low pathogenicity in mice but were highly pathogenic to chickens, as evidenced by 100% mortality 36-120 hours post infection at a low dose of 103.0EID50 and through effective contact transmission. Moreover, all three poultry H5N6 isolates caused asymptomatic infections in ducks, which may serve as a reservoir host for their maintenance and dissemination; these migrating waterfowl could cause a potential global pandemic. Our study suggests that continuous epidemiological surveillance in poultry should be implemented for the early prevention of future influenza outbreaks.

ACS Style

Kaituo Liu; Min Gu; Shunlin Hu; Ruyi Gao; Juan Li; Liwei Shi; Wenqi Sun; Dong Liu; Zhao Gao; Xiulong Xu; Jiao Hu; Xiaoquan Wang; Xiaowen Liu; Sujuan Chen; Daxin Peng; Xinan Jiao; Xiufan Liu. Genetic and biological characterization of three poultry-origin H5N6 avian influenza viruses with all internal genes from genotype S H9N2 viruses. Archives of Virology 2018, 163, 947 -960.

AMA Style

Kaituo Liu, Min Gu, Shunlin Hu, Ruyi Gao, Juan Li, Liwei Shi, Wenqi Sun, Dong Liu, Zhao Gao, Xiulong Xu, Jiao Hu, Xiaoquan Wang, Xiaowen Liu, Sujuan Chen, Daxin Peng, Xinan Jiao, Xiufan Liu. Genetic and biological characterization of three poultry-origin H5N6 avian influenza viruses with all internal genes from genotype S H9N2 viruses. Archives of Virology. 2018; 163 (4):947-960.

Chicago/Turabian Style

Kaituo Liu; Min Gu; Shunlin Hu; Ruyi Gao; Juan Li; Liwei Shi; Wenqi Sun; Dong Liu; Zhao Gao; Xiulong Xu; Jiao Hu; Xiaoquan Wang; Xiaowen Liu; Sujuan Chen; Daxin Peng; Xinan Jiao; Xiufan Liu. 2018. "Genetic and biological characterization of three poultry-origin H5N6 avian influenza viruses with all internal genes from genotype S H9N2 viruses." Archives of Virology 163, no. 4: 947-960.