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  1. Article ; Online: Single-cell RNA sequencing reveals the MIF-ACKR3 receptor-ligand interaction between iCAFs and tumor cells in esophageal squamous cell carcinoma.

    Liang, Jialu / Lei, Kai / Liang, Ruihao / Huang, Jing / Tan, Binhua / Lin, Huayue / Wang, Minghui

    Cellular signalling

    2024  Volume 117, Page(s) 111093

    Abstract: Background: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the gastrointestinal tract with a high morbidity and mortality rate. The heterogeneity of ESCC poses challenges in treatment and contributes to the poor prognosis of patients. ...

    Abstract Background: Esophageal squamous cell carcinoma (ESCC) is a malignant tumor of the gastrointestinal tract with a high morbidity and mortality rate. The heterogeneity of ESCC poses challenges in treatment and contributes to the poor prognosis of patients. Therefore, it is crucial to gain a better understanding of the tumor microenvironment (TME) heterogeneity and identify novel therapeutic targets.
    Methods: To solve this problem, we performed a single-cell RNA sequencing (scRNA-seq) analysis of ESCC samples obtained from the GEO database.
    Results: A total of 31,283 single cells were categorized into nine cell types, which included four non-immune cells (epithelial cells, endothelial cells, fibroblasts, schwann cells) and five immune cells (T cells, macrophages, mast cells, neutrophils, B cells). Our study revealed the presence of immunosuppressive tumor microenvironments in ESCC. We have also identified not only inflammatory cancer-associated fibroblast (iCAFs) and myofibroblastic cancer-associated fibroblasts (myCAFs) but also a subset of antigen presenting cancer-associated fibroblasts (apCAFs) which express high levels of HLA class II molecules in ESCC. Furthermore, our analysis of cell communication showed up-regulation of MIF-ACKR3 interaction between iCAFs and tumor cells in tumors compared to normal tissues. Finally, it was demonstrated that macrophage migration inhibitory factor (MIF) facilitates tumor cell migration and invasion through interacting with ACKR3 in vitro.
    Conclusions: This study exposes the features of the tumor microenvironment of ESCC via scRNA-seq and examines the dynamics of various cellular subpopulations, thus facilitating the identification of future therapeutic targets for ESCC.
    MeSH term(s) Humans ; Cancer-Associated Fibroblasts/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Line, Tumor ; Endothelial Cells/metabolism ; Esophageal Neoplasms/genetics ; Esophageal Neoplasms/pathology ; Esophageal Squamous Cell Carcinoma/genetics ; Esophageal Squamous Cell Carcinoma/pathology ; Intramolecular Oxidoreductases ; Ligands ; Macrophage Migration-Inhibitory Factors/genetics ; Macrophage Migration-Inhibitory Factors/metabolism ; Sequence Analysis, RNA ; Tumor Microenvironment ; Single-Cell Gene Expression Analysis
    Chemical Substances Intramolecular Oxidoreductases (EC 5.3.-) ; Ligands ; Macrophage Migration-Inhibitory Factors ; MIF protein, human (EC 5.3.2.1)
    Language English
    Publishing date 2024-02-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1002702-6
    ISSN 1873-3913 ; 0898-6568
    ISSN (online) 1873-3913
    ISSN 0898-6568
    DOI 10.1016/j.cellsig.2024.111093
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2579: Show issues Location:
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  2. Article ; Online: Comparative analysis of single-cell transcriptome reveals heterogeneity in the tumor microenvironment of lung adenocarcinoma and brain metastases.

    Liang, Jialu / Liang, Ruihao / Lei, Kai / Huang, Jing / Lin, Huayue / Wang, Minghui

    Discover. Oncology

    2023  Volume 14, Issue 1, Page(s) 174

    Abstract: Purpose: Solid tumors such as lung adenocarcinoma include not only the tumor cells but also the microenvironment in which the tumor cells continuously interact with each other. An in-depth understanding of the oncological features and tumor ... ...

    Abstract Purpose: Solid tumors such as lung adenocarcinoma include not only the tumor cells but also the microenvironment in which the tumor cells continuously interact with each other. An in-depth understanding of the oncological features and tumor microenvironment (TME) of lung adenocarcinoma and brain metastases at the single-cell level could provide new therapeutic strategies for brain metastases from lung adenocarcinoma.
    Methods: To solve this problem, we performed single-cell RNA sequencing (scRNA-seq) analysis on 15 lung adenocarcinoma samples and 10 brain metastasis samples.
    Results: A total of 86,282 single cells were obtained and divided into 8 cell types, including epithelial cells, endothelial cells, fibroblasts, oligodendrocytes, T/NK cells, B cells, mast cells, and macrophages. In brain metastases, we found a significantly lower proportion of T/NK cells and mast cells, and more severe immune dysregulation. In addition, we found a subpopulation of macrophages with high expression of metastasis-promoting-related genes enriched in brain metastatic tissues. Moreover, in brain metastases, we found a significantly increased proportion of myofibroblastic cancer-associated fibroblasts (myCAFs) and a higher angiogenic capacity of endothelial cells. Epithelial cells in brain metastases were more malignant and underwent genomic reprogramming. Next, we found that DNA damage-inducible transcript 4 (DDIT4) expression was upregulated in epithelial cells in brain metastases and was associated with poor prognosis. Finally, we experimentally validated that the downregulation of DDIT4 inhibited the proliferation, migration, and invasion of lung cancer cells.
    Conclusions: This study depicts a single-cell atlas of lung adenocarcinoma and brain metastases by scRNA-seq and paves the way for the development of future therapeutic targets for brain metastases from lung cancer.
    Language English
    Publishing date 2023-09-15
    Publishing country United States
    Document type Journal Article
    ISSN 2730-6011
    ISSN (online) 2730-6011
    DOI 10.1007/s12672-023-00784-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A novel protein encoded by circUBE4B promotes progression of esophageal squamous cell carcinoma by augmenting MAPK/ERK signaling.

    Lyu, Yingcheng / Tan, Binghua / Li, Lin / Liang, Ruihao / Lei, Kai / Wang, Kefeng / Wu, Duoguang / Lin, Huayue / Wang, Minghui

    Cell death & disease

    2023  Volume 14, Issue 6, Page(s) 346

    Abstract: Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins ... ...

    Abstract Esophageal squamous carcinoma (ESCC) is a common malignant cancer. Although the non-coding roles of circRNAs in the pathogenesis of human tumors have been well studied, whether circRNAs participate in the progression of ESCC by encoding novel proteins remains unclear. In this study, we identified an overexpression circRNA with protein-coding ability in ESCC tissues, called circUBE4B, whose expression level is correlated with tumor size and tumor differentiation level of ESCC patients. Moreover, a higher level of circUBE4B in ESCC patients is correlated with a worse prognosis. Functionally, we found that circUBE4B promoted the proliferation of ESCC cells by encoding a novel cancer-promoting protein, circUBE4B-173aa. Mechanistically, the circUBE4B-173aa protein interacts with MAPK1 and promotes the phosphorylation level of MAPK1 to eventually activate MAPK/ERK signaling pathway. The xenograft model revealed that overexpression of circUBE4B-173aa in ESCC cells significantly promoted the growth of grafts. Our study provides new insights into the mechanism of circRNA in the development of ESCC and circUBE4B-173aa has the potential to serve as a biomarker and a novel therapeutic target for ESCC therapy.
    MeSH term(s) Humans ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Esophageal Neoplasms/pathology ; Esophageal Squamous Cell Carcinoma/pathology ; Gene Expression Regulation, Neoplastic/genetics ; RNA, Circular/genetics ; Signal Transduction/genetics
    Chemical Substances RNA, Circular ; UBE4B protein, human (EC 2.3.2.27)
    Language English
    Publishing date 2023-06-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-05865-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: LncRNA NRON promotes tumorigenesis by enhancing MDM2 activity toward tumor suppressor substrates.

    Guo, Qiannan / Li, Yihui / Zhang, Yunmei / Shen, Liping / Lin, Huayue / Chen, Jianing / Song, Erwei / Luo, Man-Li

    The EMBO journal

    2023  Volume 42, Issue 16, Page(s) e112414

    Abstract: The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor-suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53- ... ...

    Abstract The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor-suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops, respectively, and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 toward its tumor-suppressing substrates, including P53, RB1, and NFAT1. NRON knockdown dramatically inhibits tumor cell growth in vitro and in vivo. More importantly, NRON overexpression promotes oncogenic transformation by inducing anchorage-independent growth in vitro and facilitating tumor formation in immunocompromised mice. Clinically, NRON expression is significantly associated with poor clinical outcome in breast cancer patients. Together, our data uncover a pivotal role of lncRNA that induces malignant transformation of epithelial cells by inhibiting multiple tumor suppressor proteins.
    MeSH term(s) Animals ; Mice ; Carcinogenesis/genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics ; Proto-Oncogene Proteins c-mdm2/genetics ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Chemical Substances Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; RNA, Long Noncoding ; Tumor Suppressor Protein p53 ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Mdm2 protein, mouse (EC 2.3.2.27) ; NRON long non-coding RNA, mouse
    Language English
    Publishing date 2023-06-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.15252/embj.2022112414
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1808: Show issues Location:
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  5. Article ; Online: Tumor-derived apoptotic extracellular vesicle-mediated intercellular communication promotes metastasis and stemness of lung adenocarcinoma.

    He, Xiaotian / Ma, Yiyang / Wen, Yingsheng / Zhang, Rusi / Zhao, Dechang / Wang, Gongming / Wang, Weidong / Huang, Zirui / Guo, Guangran / Zhang, Xuewen / Lin, Huayue / Zhang, Lanjun

    Bioactive materials

    2024  Volume 36, Page(s) 238–255

    Abstract: Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation, and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors. Moreover, tumor-derived apoptotic extracellular vesicles (apoEVs) ...

    Abstract Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation, and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors. Moreover, tumor-derived apoptotic extracellular vesicles (apoEVs) are inevitably phagocytosed by live tumor cells, promoting tumor heterogeneity. Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence. Herein, we conducted a series of in vivo and in vitro experiments, and we report that tumor-derived apoEVs promoted lung adenocarcinoma (LUAD) metastasis, self-renewal and chemoresistance. Mechanistically, we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2. In addition, we found that ALDH1A1, which was transported by apoEVs, activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells. Furthermore, targeting apoEVs-ALDH1A1 significantly abrogated these effects. Collectively, our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations, and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.
    Language English
    Publishing date 2024-03-06
    Publishing country China
    Document type Journal Article
    ISSN 2452-199X
    ISSN (online) 2452-199X
    DOI 10.1016/j.bioactmat.2024.02.026
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  6. Article ; Online: CircPDE5A-encoded novel regulator of the PI3K/AKT pathway inhibits esophageal squamous cell carcinoma progression by promoting USP14-mediated de-ubiquitination of PIK3IP1.

    Lei, Kai / Liang, Ruihao / Liang, Jialu / Lu, Nan / Huang, Jing / Xu, Ke / Tan, Binghua / Wang, Kexi / Liang, Yicheng / Wang, Wenjian / Lin, Huayue / Wang, Minghui

    Journal of experimental & clinical cancer research : CR

    2024  Volume 43, Issue 1, Page(s) 124

    Abstract: Background: Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal tumor and has become an important global health problem. The PI3K/AKT signaling pathway plays a key role in the development of ESCC. CircRNAs have been reported to be ... ...

    Abstract Background: Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal tumor and has become an important global health problem. The PI3K/AKT signaling pathway plays a key role in the development of ESCC. CircRNAs have been reported to be involved in the regulation of the PI3K/AKT pathway, but the underlying mechanisms are unclear. Therefore, this study aimed to identify protein-coding circRNAs and investigate their functions in ESCC.
    Methods: Differential expression of circRNAs between ESCC tissues and adjacent normal tissues was identified using circRNA microarray analysis. Thereafter, LC-MS/MS was used to identify circPDE5A-encoded novel protein PDE5A-500aa. Molecular biological methods were used to explore the biological functions and regulatory mechanisms of circPDE5A and PDE5A-500aa in ESCC. Lastly, circRNA-loaded nanoplatforms were constructed to investigate the therapeutic translation value of circPDE5A.
    Results: We found that circPDE5A expression was down-regulated in ESCC cells and tissues and that it was negatively associated with advanced clinicopathological stages and poorer prognosis in ESCC. Functionally, circPDE5A inhibited ESCC proliferation and metastasis in vitro and in vivo by encoding PDE5A-500aa, a key regulator of the PI3K/AKT signaling pathway in ESCC. Mechanistically, PDE5A-500aa interacted with PIK3IP1 and promoted USP14-mediated de-ubiquitination of the k48-linked polyubiquitin chain at its K198 residue, thereby attenuating the PI3K/AKT pathway in ESCC. In addition, Meo-PEG-S-S-PLGA-based reduction-responsive nanoplatforms loaded with circPDE5A and PDE5A-500aa plasmids were found to successfully inhibit the growth and metastasis of ESCC in vitro and in vivo.
    Conclusion: The novel protein PDE5A-500aa encoded by circPDE5A can act as an inhibitor of the PI3K/AKT signaling pathway to inhibit the progression of ESCC by promoting USP14-mediated de-ubiquitination of PIK3IP1 and may serve as a potential target for the development of therapeutic agents.
    MeSH term(s) Animals ; Female ; Humans ; Male ; Mice ; Middle Aged ; Cell Line, Tumor ; Cell Proliferation ; Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5/genetics ; Disease Progression ; Esophageal Neoplasms/metabolism ; Esophageal Neoplasms/pathology ; Esophageal Neoplasms/genetics ; Esophageal Squamous Cell Carcinoma/pathology ; Esophageal Squamous Cell Carcinoma/metabolism ; Esophageal Squamous Cell Carcinoma/genetics ; Mice, Nude ; Phosphatidylinositol 3-Kinases/metabolism ; Prognosis ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Circular/genetics ; RNA, Circular/metabolism ; Signal Transduction ; Ubiquitin Thiolesterase/metabolism ; Ubiquitin Thiolesterase/genetics ; Ubiquitination
    Chemical Substances Cyclic Nucleotide Phosphodiesterases, Type 5 (EC 3.1.4.35) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; RNA, Circular ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; USP14 protein, human ; PDE5A protein, human (EC 3.1.4.35) ; PIK3IP1 protein, human
    Language English
    Publishing date 2024-04-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 803138-1
    ISSN 1756-9966 ; 0392-9078
    ISSN (online) 1756-9966
    ISSN 0392-9078
    DOI 10.1186/s13046-024-03054-3
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    Zs.A 2065: Show issues Location:
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  7. Article ; Online: Corrigendum to "CCL18-induced HOTAIR upregulation promotes malignant progression in esophageal squamous cell carcinoma through the miR-130a-5p-ZEB1 axis" [Cancer Lett. 460 (2019) 18-28].

    Wang, Wenjian / Wu, Duoguang / He, Xiaotian / Hu, Xueting / Hu, Chuwen / Shen, Zhiwen / Lin, Jiatong / Pan, Zihao / He, Zhanghai / Lin, Huayue / Wang, Minghui

    Cancer letters

    2024  , Page(s) 216910

    Language English
    Publishing date 2024-05-02
    Publishing country Ireland
    Document type Published Erratum
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2024.216910
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    Zs.A 1177: Show issues Location:
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  8. Article: The FGF6 amplification mutation plays an important role in the progression and treatment of malignant meningioma.

    Liang, Ruihao / Tan, Binhua / Lei, Kai / Xu, Ke / Liang, Jialu / Huang, Jing / Liang, Yicheng / Huang, Jintao / Zhang, Liwen / Shi, Xiaoliang / Lv, Zhiqiang / Lin, Huayue / Wang, Minghui

    Translational oncology

    2024  Volume 45, Page(s) 101974

    Abstract: Meningioma is a benign tumor with slow growth and long course. However, patients with recurrent malignant meningioma still face a lack of effective treatment. Here, we report a rare case of primary mediastinal malignant meningioma with lung and bone ... ...

    Abstract Meningioma is a benign tumor with slow growth and long course. However, patients with recurrent malignant meningioma still face a lack of effective treatment. Here, we report a rare case of primary mediastinal malignant meningioma with lung and bone metastases, who benefited from the treatment of apatinib (≥33 months) and anlotinib (until the publication date). Retrospective molecular analysis revealed the frequent amplification of FGF6 in primary and metastatic lesions. Then we constructed the FGF6 over-expressed IOMM-LEE and CH157MN malignant meningioma cell lines, and in vitro and vivo experiments showed that overexpression of FGF6 can promote the proliferation, migration and invasion of malignant meningioma cells. Based on the Western analysis, we revealed that FGF6 can promote the phosphorylation of FGFR, AKT, and ERK1/2, which can be inhibited by anlotinib. Together, we were the first to verify that overexpression of FGF6 promotes the progression of malignant meningiomas by activating FGFR/AKT/ERK1/2 pathway and pointed out that anlotinib may effectively inhibit the disease progression of patients with FGF6 amplification.
    Language English
    Publishing date 2024-05-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2443840-6
    ISSN 1936-5233
    ISSN 1936-5233
    DOI 10.1016/j.tranon.2024.101974
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  9. Article ; Online: SARS-CoV-2 main protease suppresses type I interferon production by preventing nuclear translocation of phosphorylated IRF3.

    Fung, Sin-Yee / Siu, Kam-Leung / Lin, Huayue / Yeung, Man Lung / Jin, Dong-Yan

    International journal of biological sciences

    2021  Volume 17, Issue 6, Page(s) 1547–1554

    Abstract: Suppression of type I interferon (IFN) response is one pathological outcome of the infection of highly pathogenic human coronaviruses. To effect this, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 encode multiple IFN antagonists. ...

    Abstract Suppression of type I interferon (IFN) response is one pathological outcome of the infection of highly pathogenic human coronaviruses. To effect this, severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 encode multiple IFN antagonists. In this study, we reported on the IFN antagonism of SARS-CoV-2 main protease NSP5. NSP5 proteins of both SARS-CoV and SARS-CoV-2 counteracted Sendai virus-induced IFN production. NSP5 variants G15S and K90R commonly seen in circulating strains of SARS-CoV-2 retained the IFN-antagonizing property. The suppressive effect of NSP5 on IFN-β gene transcription induced by RIG-I, MAVS, TBK1 and IKKϵ suggested that NSP5 likely acts at a step downstream of IRF3 phosphorylation in the cytoplasm. NSP5 did not influence steady-state expression or phosphorylation of IRF3, suggesting that IRF3, regardless of its phosphorylation state, might not be the substrate of NSP5 protease. However, nuclear translocation of phosphorylated IRF3 was severely compromised in NSP5-expressing cells. Taken together, our work revealed a new mechanism by which NSP5 proteins encoded by SARS-CoV and SARS-CoV-2 antagonize IFN production by retaining phosphorylated IRF3 in the cytoplasm. Our findings have implications in rational design and development of antiviral agents against SARS-CoV-2.
    MeSH term(s) Animals ; COVID-19/virology ; Cell Nucleus/metabolism ; Chlorocebus aethiops ; Coronavirus 3C Proteases/metabolism ; Humans ; Interferon Regulatory Factor-3/metabolism ; Interferon Type I/biosynthesis ; Phosphorylation ; Protein Transport ; SARS-CoV-2/enzymology ; Vero Cells
    Chemical Substances IRF3 protein, human ; Interferon Regulatory Factor-3 ; Interferon Type I ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2021-04-10
    Publishing country Australia
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2179208-2
    ISSN 1449-2288 ; 1449-2288
    ISSN (online) 1449-2288
    ISSN 1449-2288
    DOI 10.7150/ijbs.59943
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  10. Article: SARS-CoV-2 NSP13 helicase suppresses interferon signaling by perturbing JAK1 phosphorylation of STAT1.

    Fung, Sin-Yee / Siu, Kam-Leung / Lin, Huayue / Chan, Ching-Ping / Yeung, Man Lung / Jin, Dong-Yan

    Cell & bioscience

    2022  Volume 12, Issue 1, Page(s) 36

    Abstract: Background: SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result ... ...

    Abstract Background: SARS-CoV-2 is the causative agent of COVID-19. Overproduction and release of proinflammatory cytokines are the underlying cause of severe COVID-19. Treatment of this condition with JAK inhibitors is a double-edged sword, which might result in the suppression of proinflammatory cytokine storm and the concurrent enhancement of viral infection, since JAK signaling is essential for host antiviral response. Improving the current JAK inhibitor therapy requires a detailed molecular analysis on how SARS-CoV-2 modulates interferon (IFN)-induced activation of JAK-STAT signaling.
    Results: In this study, we focused on the molecular mechanism by which SARS-CoV-2 NSP13 helicase suppresses IFN signaling. Expression of SARS-CoV-2 NSP13 alleviated transcriptional activity driven by type I and type II IFN-responsive enhancer elements. It also prevented nuclear translocation of STAT1 and STAT2. The suppression of NSP13 on IFN signaling occurred at the step of STAT1 phosphorylation. Nucleic acid binding-defective mutant K345A K347A and NTPase-deficient mutant E375A of NSP13 were found to have largely lost the ability to suppress IFN-β-induced STAT1 phosphorylation and transcriptional activation, indicating the requirement of the helicase activity for NSP13-mediated inhibition of STAT1 phosphorylation. NSP13 did not interact with JAK1 nor prevent STAT1-JAK1 complex formation. Mechanistically, NSP13 interacted with STAT1 to prevent JAK1 kinase from phosphorylating STAT1.
    Conclusion: SARS-CoV-2 NSP13 helicase broadly suppresses IFN signaling by targeting JAK1 phosphorylation of STAT1.
    Language English
    Publishing date 2022-03-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 2593367-X
    ISSN 2045-3701
    ISSN 2045-3701
    DOI 10.1186/s13578-022-00770-1
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