scholarly journals Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao Man Wu ◽  
Hong Fang ◽  
Jie Zhang ◽  
Yong Hong Bi ◽  
Ming Xian Chang
Keyword(s):  
Immune Response ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Early Stage ◽  
Negative Regulation ◽  
Histone H2a ◽  
Antiviral Immune Response ◽  
Functional Complex ◽  
Host Innate Immune Response

Histone H2A is a nuclear molecule tightly associated in the form of the nucleosome. Our previous studies have demonstrated the antibacterial property of piscine H2A variants against gram-negative bacteria Edwardsiella piscicida and Gram-positive bacteria Streptococcus agalactiae. In this study, we show the function and mechanism of piscine H2A in the negative regulation of RLR signaling pathway and host innate immune response against spring viremia of carp virus (SVCV) infection. SVCV infection significantly inhibits the expression of histone H2A during an early stage of infection, but induces the expression of histone H2A during the late stage of infection such as at 48 and 72 hpi. Under normal physiological conditions, histone H2A is nuclear-localized. However, SVCV infection promotes the migration of histone H2A from the nucleus to the cytoplasm. The in vivo studies revealed that histone H2A overexpression led to the increased expression of SVCV gene and decreased survival rate. The overexpression of histone H2A also significantly impaired the expression levels of those genes involved in RLR antiviral signaling pathway. Furthermore, histone H2A targeted TBK1 and IRF3 to promote their protein degradation via the lysosomal pathway and impair the formation of TBK1-IRF3 functional complex. Importantly, histone H2A completely abolished TBK1-mediated antiviral activity and enormously impaired the protein expression of IRF3, especially nuclear IRF3. Further analysis demonstrated that the inhibition of histone H2A nuclear/cytoplasmic trafficking could relieve the protein degradation of TBK1 and IRF3, and blocked the negative regulation of histone H2A on the SVCV infection. Collectively, our results suggest that histone H2A nuclear/cytoplasmic trafficking is essential for negative regulation of RLR signaling pathway and antiviral immune response in response to SVCV infection.

A Janus Kinase in the JAK/STAT signaling pathway from Litopenaeus vannamei is involved in antiviral immune response

2015 ◽  
Vol 44 (2) ◽  
pp. 662-673 ◽  
Author(s):  
Xuan Song ◽  
Zijian Zhang ◽  
Sheng Wang ◽  
Haoyang Li ◽  
Hongliang Zuo ◽  
...  
Keyword(s):  
Immune Response ◽  
Signaling Pathway ◽  
Litopenaeus Vannamei ◽  
Janus Kinase ◽  
Antiviral Immune Response ◽  
Stat Signaling

Negative regulation of the innate antiviral immune response by TRIM62 from orange spotted grouper

2016 ◽  
Vol 57 ◽  
pp. 68-78 ◽  
Author(s):  
Ying Yang ◽  
Youhua Huang ◽  
Yepin Yu ◽  
Sheng Zhou ◽  
Shaowen Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Negative Regulation ◽  
Antiviral Immune Response

scholarly journals Grouper TRIM13 exerts negative regulation of antiviral immune response against nodavirus

2016 ◽  
Vol 55 ◽  
pp. 106-115 ◽  
Author(s):  
Youhua Huang ◽  
Min Yang ◽  
Yepin Yu ◽  
Ying Yang ◽  
Linli Zhou ◽  
...  
Keyword(s):  
Immune Response ◽  
Negative Regulation ◽  
Antiviral Immune Response

scholarly journals Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Dandan Qi ◽  
Lei Hu ◽  
Tong Jiao ◽  
Tinghong Zhang ◽  
Xiaomei Tong ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Phosphatase Activity ◽  
Signaling Pathway ◽  
Sendai Virus ◽  
Rna Virus ◽  
Negative Regulator ◽  
Luciferase Assay ◽  
Dna Virus ◽  
Antiviral Immune Response

ABSTRACT The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-β) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-β stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-β. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-β reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity. IMPORTANCE The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-β transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

scholarly journals Immunoglobulin G Antibody-Mediated Enhancement of Measles Virus Infection Can Bypass the Protective Antiviral Immune Response

2006 ◽  
Vol 80 (17) ◽  
pp. 8530-8540 ◽  
Author(s):  
Ianko D. Iankov ◽  
Manoj Pandey ◽  
Mary Harvey ◽  
Guy E. Griesmann ◽  
Mark J. Federspiel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Response ◽  
Immunoglobulin G ◽  
Measles Virus ◽  
Host Cells ◽  
Igg Antibodies ◽  
Inhibitory Peptide ◽  
Host Cell Membrane ◽  
Antiviral Immune Response

ABSTRACT Antibodies to viral surface glycoproteins play a crucial role in immunity to measles by blocking both virus attachment and subsequent fusion with the host cell membrane. Here, we demonstrate that certain immunoglobulin G (IgG) antibodies can also enhance the entry of measles virus (MV) into monocytes and macrophages. Antibody-dependent enhancement of infectivity was observed in mouse and human macrophages using virions opsonized by a murine monoclonal antibody against the MV hemagglutinin (H) glycoprotein, polyclonal mouse anti-MV IgG, or diluted measles-immune human sera. Neither H-specific Fab fragments nor H-specific IgM could enhance MV entry in monocytes or macrophages, indicating involvement of a Fc γ receptor (FcγR)-mediated mechanism. Preincubation with an anti-fusion protein (anti-F) monoclonal antibody or a fusion-inhibitory peptide blocked infection, indicating that a functional F protein was required for viral internalization. Classical complement pathway activation did not promote infection through complement receptors and inhibited anti-H IgG-mediated enhancement. In vivo, antibody-enhanced infection allowed MV to overcome a highly protective systemic immune response in preimmunized IfnarKo-Ge46 transgenic mice. These data demonstrate a previously unidentified mechanism that may contribute to morbillivirus pathogenesis where H-specific IgG antibodies promote the spread of MV infection among FcγR-expressing host cells. The findings point to a new model for the pathogenesis of atypical MV infection observed after immunization with formalin-inactivated MV vaccine and underscore the importance of the anti-F response after vaccination.

770 THE HCV NS3/4A-MEDIATED IMPAIRMENT OF THE HEPATIC ANTIVIRAL IMMUNE RESPONSE IS REVERSED BY PROTEASE INHIBITION OR RIBAVIRIN IN VIVO

2012 ◽  
Vol 56 ◽  
pp. S302
Author(s):  
E.D. Brenndörfer ◽  
A. Brass ◽  
J. Söderholm ◽  
L. Frelin ◽  
J.G. Bode ◽  
...  
Keyword(s):  
Immune Response ◽  
Protease Inhibition ◽  
Antiviral Immune Response

scholarly journals The Virus-Encoded Chemokine vMIP-II Inhibits Virus-Induced Tc1-Driven Inflammation

2003 ◽  
Vol 77 (13) ◽  
pp. 7393-7400 ◽  
Author(s):  
Morten Lindow ◽  
Anneline Nansen ◽  
Christina Bartholdy ◽  
Annette Stryhn ◽  
Nils J. V. Hansen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Human Herpesvirus ◽  
Delayed Type Hypersensitivity ◽  
Intravenous Route ◽  
Antiviral Immune Response

ABSTRACT The human herpesvirus 8-encoded protein vMIP-II is a potent in vitro antagonist of many chemokine receptors believed to be associated with attraction of T cells with a type 1 cytokine profile. For the present report we have studied the in vivo potential of this viral chemokine antagonist to inhibit virus-induced T-cell-mediated inflammation. This was done by use of the well-established model system murine lymphocytic choriomeningitis virus infection. Mice were infected in the footpad, and the induced CD8+ T-cell-dependent inflammation was evaluated in mice subjected to treatment with vMIP-II. We found that inflammation was markedly inhibited in mice treated during the efferent phase of the antiviral immune response. In vitro studies revealed that vMIP-II inhibited chemokine-induced migration of activated CD8+ T cells, but not T-cell-target cell contact, granule exocytosis, or cytokine release. Consistent with these in vitro findings treatment with vMIP-II inhibited the adoptive transfer of a virus-specific delayed-type hypersensitivity response in vivo, but only when antigen-primed donor cells were transferred via the intravenous route and required to migrate actively, not when the cells were injected directly into the test site. In contrast to the marked inhibition of the effector phase, the presence of vMIP-II during the afferent phase of the immune response did not result in significant suppression of virus-induced inflammation. Taken together, these results indicate that chemokine-induced signals are pivotal in directing antiviral effector cells toward virus-infected organ sites and that vMIP-II is a potent inhibitor of type 1 T-cell-mediated inflammation.

Grouper TRAF5 exerts negative regulation on antiviral immune response against Iridovirus

2021 ◽  
Author(s):  
Mengshi Sun ◽  
Siting Wu ◽  
Xin Zhang ◽  
Luhao Zhang ◽  
Shaozhu Kang ◽  
...  
Keyword(s):  
Immune Response ◽  
Negative Regulation ◽  
Antiviral Immune Response

scholarly journals HVEM Promotes the Osteogenesis of allo-MSCs by Inhibiting the Secretion of IL-17 and IFN-γ in Vγ4T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Lei He ◽  
Jun Xiao ◽  
Lei Song ◽  
Rui Zhou ◽  
Zhigang Rong ◽  
...  
Keyword(s):  
Immune Response ◽  
Osteogenic Differentiation ◽  
Bone Repair ◽  
Culture Supernatant ◽  
Early Stage ◽  
Bone Defects ◽  
Interleukin 17 ◽  
Ifn Γ

Bone defects are a common orthopaedic concern, and an increasing number of tissue-engineered bones (TEBs) are used to repair bone defects. Allogeneic mesenchymal stem cells (allo-MSCs) are used as seed cells in many approaches to develop TEB constructs, but the immune response caused by allogeneic transplantation may lead to transplant failure. V gamma 4 T (Vγ4T) cells play an important role in mediating the immune response in the early stage after transplantation; therefore, we wanted to verify whether suppressing Vγ4T cells by herpesvirus entry mediator (HVEM)/B and T lymphocyte attenuator (BTLA) signalling can promote MSCs osteogenesis in the transplanted area. In vitro experiments showed that the osteogenic differentiation of MSCs and Vγ4T cells was weakened after co-culture, and an increase in interleukin-17 (IL-17) and interferon-γ (IFN-γ) levels was detected in the culture supernatant. HVEM-transfected MSCs (MSCs-HVEM) still exhibited osteogenic differentiation activity after co-culture with Vγ4T cells, and the levels of IL-17 and IFN-γ in the co-culture supernatant were significantly reduced. In vivo experiments revealed that inflammation in the transplanted area was reduced and osteogenic repair was enhanced after Vγ4T cells were removed. MSCs-HVEM can also consistently contribute to reduced inflammation in the transplanted area and enhanced bone repair in wild-type (WT) mice. Therefore, our experiments verified that HVEM can promote the osteogenesis of allo-MSCs by inhibiting IL-17 and IFN-γ secretion from Vγ4T cells.

scholarly journals GRP75-upregulated HMGA1 Expression Promotes Stage I Lung Adenocarcinoma Progression by Activating the JNK/c-JUN Signaling Pathway

2020 ◽  
Author(s):  
Guo-Bing Qiao ◽  
Ren-Tao Wang ◽  
Shu-Nan Wang ◽  
Shaolin Tao ◽  
Qun-You Tan ◽  
...  
Keyword(s):  
Cell Growth ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Early Stage ◽  
High Mobility ◽  
Stage I ◽  
Sequencing Analysis ◽  
Hmga1 Expression

Abstract Background: Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. However, the recurrence mechanism is still unclear, and no biomarkers can predict recurrence in early-stage LUAD. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.Methods: A TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. Western blotting and immunohistochemistry were used to measure protein expression levels. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis.Results: High expression of HMGA1 and GRP75 was associated with recurrence and a poor prognosis in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor. Overexpression of GRP75 or HMGA1 promoted LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis. In vitro and clinical data showed that the expression level of GRP75 positively regulated HMGA1 in LUAD and that GRP75 played an HMGA1-dependent role. In addition, GRP75 prolonged the half-life of HMGA1 by inhibiting HMGA1 ubiquitination via direct binding to HMGA1. Finally, we demonstrated that the GRP75/HMGA1 axis played a role by activating JNK/c-JUN signaling in LUAD.Conclusions: The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and prognosis in patients with stage I LUAD.

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