非洲猪瘟病毒(African swine fever virus,ASFV)p22是一种内囊膜蛋白,尽管其意义重大,但其功能解析仍然未有报道。2025年7月16日,河南农业大学动物医学学院张改平院士研究团队在PLoSPathogens杂志发表了题为“The African swine fever v...非洲猪瘟病毒(African swine fever virus,ASFV)p22是一种内囊膜蛋白,尽管其意义重大,但其功能解析仍然未有报道。2025年7月16日,河南农业大学动物医学学院张改平院士研究团队在PLoSPathogens杂志发表了题为“The African swine fever virus p22 inhibits the JAK-STAT signaling pathway by promoting the TAX1BP1-mediated degradation of the type I interferon receptor”的研究论文。该研究发现非洲猪瘟病毒p22蛋白能够显著抑制宿主细胞JAK-STAT信号通路的激活;揭示了干扰素受体IFNAR1的一种新的自噬降解机制。展开更多
Summary： The type I interferon and IFNAR play an important role in hepatitis B virus （HBV） infection and anti-HBV therapy. However, its mechanism of action is still poorly understood. To gain more in- sights into t...Summary： The type I interferon and IFNAR play an important role in hepatitis B virus （HBV） infection and anti-HBV therapy. However, its mechanism of action is still poorly understood. To gain more in- sights into the role of type I interferon and type I interferon receptor （IFNAR） in HBV infection, we established an HBV persistent replication IFNAR knockout （IFNAR-/-） mouse model and preliminarily applied this model. At first, the progeny of IFNAR-/- mouse was reproduced. Then hydrodynamic injec- tion with pAAV/HBV1.2 plasmid was conducted to establish the persistent HBV replication IFNAR-/- mouse model. At last, we applied this model to evaluate the effect of nucleoside analogues entecavir （ETV） on HBV replication. It was found that there was no difference in the serum HBsAg and HBeAg levels and HBcAg expression in the liver tissue between the ETV treated groups and normal saline （NS） treated group, but the serum HBV DNA levels were significantly suppressed 10, 25, 40 and 55 days af- ter the ETV treatment [P=0.035, P=0.00, P=0.149 and P=-0.084, IFNAR knockout （KO） control group vs. C57BL/6 ETV groups, respectively; P=0.081, P=0.001, P=0.243 and P=-0.147, IFNAR KO control group vs. IFNAR KO ETV groups, respectively]. Interestingly, there was no difference in serum HBV DNA levels between the ETV treated IFNAR/- and C57BL/6 mice. This result suggests that HBV sup- pression during ETV treatments doesn＇t depend on type Ⅰinterferon and IFNAR. Collectively, persis- tent HBV replication IFNAR/ mouse model that we established is a useful and convenient tool to detect the function of the type Ⅰ interferon and IFNAR in HBV infection and anti-HBV treatments.展开更多
Enterovirus A71(EV-A71) is the major pathogen responsible for the severe hand, foot and mouth disease worldwide, for which few effective antiviral drugs are presently available. Interferon-a(IFN-a) has been used in an...Enterovirus A71(EV-A71) is the major pathogen responsible for the severe hand, foot and mouth disease worldwide, for which few effective antiviral drugs are presently available. Interferon-a(IFN-a) has been used in antiviral therapy for decades;it has been reported that EV-A71 antagonizes the antiviral activity of IFN-a based on viral 2 Apro-mediated reduction of the interferon-alpha receptor 1(IFNAR1);however, the mechanism remains unknown. Here, we showed a significant increase in IFNAR1 protein induced by IFN-a in RD cells, whereas EV-A71 infection caused obvious downregulation of the IFNAR1 protein and blockage of IFN-a signaling. Subsequently, we observed that EV-A71 2 Apro inhibited IFNAR1 translation by cleavage of the eukaryotic initiation factor 4 GI(eIF4GI), without affecting IFNAR1 m RNA levels induced by IFN-a. The inhibition of IFNAR1 translation also occurred in puromycin-induced apoptotic cells when caspase-3 cleaved e IF4 GI. Importantly, we verified that 2 Aprocould activate cellular caspase-3, which was subsequently involved in e IF4 GI cleavage mediated by 2 Apro. Furthermore, inhibition of caspase-3 activation resulted in the partial restoration of IFNAR1 in cells transfected with 2 A or infected with EV-A71, suggesting the pivotal role of both viral 2 Aproand caspase-3 activation in the disturbance of IFN-a signaling. Collectively, we elucidate a novel mechanism by which cellular caspase-3 contributes to viral 2 Apro-mediated down-regulation of IFNAR1 at the translation level during EV-A71 infection, indicating that caspase-3 inhibition could be a potential complementary strategy to improve clinical anti-EV-A71 therapy with IFN-a.展开更多
Casein kinase 1α(CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1(IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus(HBV) replication and the anti...Casein kinase 1α(CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1(IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus(HBV) replication and the anti-HBV effects of IFN-α are less reported. Here we show that CK1α can interact with IFNAR1 in hepatoma carcinoma cells and increased the abundance of IFNAR1 by reducing the ubiquitination levels in the presence of HBV.Furthermore, CK1α promotes the IFN-α triggered JAK-STAT signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Our results collectively provide evidence that CK1α positively regulates the anti-HBV activity of IFN-α in hepatoma carcinoma cells, which would be a promising therapeutic target to improve the effectiveness of IFN-α therapy to cure CHB.展开更多
Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis s...Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals.展开更多
Genome-wide association analysis allows the identification of potential candidate genes involved in the development of severe coronavirus disease 2019(COVID-19).Hence,it seems that genetics matters here,as well.Nevert...Genome-wide association analysis allows the identification of potential candidate genes involved in the development of severe coronavirus disease 2019(COVID-19).Hence,it seems that genetics matters here,as well.Nevertheless,the virus's nature,including its RNA structure,determines the rate of mutations leading to new viral strains with all epidemiological and clinical consequences.Given these observations,we herein comment on the current hypotheses about the possible role of the genes in association with COVID-19 severity.We discuss some of the major candidate genes that have been identified as potential genetic factors associated with the COVID-19 severity and infection susceptibility:HLA,ABO,ACE2,TLR7,ApoE,TYK2,OAS,DPP9,IFNAR2,CCR2,etc.Further study of genes and genetic variants will be of great benefit for the prevention and assessment of the individual risk and disease severity in different populations.These scientific data will serve as a basis for the development of clinically applicable diagnostic and prognostic tests for patients at high risk of COVID-19.展开更多
Direct conversion of cardiac fibroblasts(CFs)to cardiomyocytes(CMs)in vivo to regenerate heart tissue is an attractive approach.After myocardial infarction(MI),heart repair proceeds with an inflammation stage initiate...Direct conversion of cardiac fibroblasts(CFs)to cardiomyocytes(CMs)in vivo to regenerate heart tissue is an attractive approach.After myocardial infarction(MI),heart repair proceeds with an inflammation stage initiated by monocytes infiltration of the infarct zone establishing an immune microenvironment.However,whether and how the MI microenvironment influences the reprogramming of CFs remains unclear.Here,we found that in comparison with cardiac fibroblasts(CFs)cultured in vitro,CFs that transplanted into infarct region of MI mouse models resisted to cardiac reprogramming.RNA-seq analysis revealed upregulation of interferon(IFN)response genes in transplanted CFs,and subsequent inhibition of the IFN receptors increased reprogramming efficiency in vivo.Macrophage-secreted IFN-βwas identified as the dominant upstream signaling factor after MI.CFs treated with macrophage-conditioned medium containing IFN-βdisplayed reduced reprogramming efficiency,while macrophage depletion or blocking the IFN signaling pathway after MI increased reprogramming efficiency in vivo.Co-IP,BiFC and Cut-tag assays showed that phosphorylated STAT1 downstream of IFN signaling in CFs could interact with the reprogramming factor GATA4 and inhibit the GATA4 chromatin occupancy in cardiac genes.Furthermore,upregulation of IFN-IFNAR-p-STAT1 signaling could stimulate CFs secretion of CCL2/7/12 chemokines,subsequently recruiting IFN-β-secreting macrophages.Together,these immune cells further activate STAT1 phosphorylation,enhancing CCL2/7/12 secretion and immune cell recruitment,ultimately forming a self-reinforcing positive feedback loop between CFs and macrophages via IFN-IFNAR-p-STAT1 that inhibits cardiac reprogramming in vivo.Cumulatively,our findings uncover an intercellular self-stimulating inflammatory circuit as a microenvironmental molecular barrier of in situ cardiac reprogramming that needs to be overcome for regenerative medicine applications.展开更多
Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral ac...Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral activity.SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling.Mechanistically,SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8,consequently restricting the interaction between USP8 and IFNAR2.The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation,thus attenuating IFN-I antiviral activity.Correspondingly,the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2,leading to a reduction in IFNAR2 ubiquitination and,consequently,an enhancement in IFN-I-induced signaling.This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.展开更多
文摘非洲猪瘟病毒(African swine fever virus,ASFV)p22是一种内囊膜蛋白,尽管其意义重大,但其功能解析仍然未有报道。2025年7月16日,河南农业大学动物医学学院张改平院士研究团队在PLoSPathogens杂志发表了题为“The African swine fever virus p22 inhibits the JAK-STAT signaling pathway by promoting the TAX1BP1-mediated degradation of the type I interferon receptor”的研究论文。该研究发现非洲猪瘟病毒p22蛋白能够显著抑制宿主细胞JAK-STAT信号通路的激活;揭示了干扰素受体IFNAR1的一种新的自噬降解机制。
基金supported by grants from the National Natural Science Foundation of China (No. 81001313)China Postdoctoral Science Foundation (No. 2009046094)+2 种基金National Science and Technology Major Projects (No. 2008ZX10002-011)National Key Basic Research Program of China (Nos. 2007CB512804 and 2009CB522506)International Science and Technology Cooperation Program (No. 2011DFA31030)
文摘Summary： The type I interferon and IFNAR play an important role in hepatitis B virus （HBV） infection and anti-HBV therapy. However, its mechanism of action is still poorly understood. To gain more in- sights into the role of type I interferon and type I interferon receptor （IFNAR） in HBV infection, we established an HBV persistent replication IFNAR knockout （IFNAR-/-） mouse model and preliminarily applied this model. At first, the progeny of IFNAR-/- mouse was reproduced. Then hydrodynamic injec- tion with pAAV/HBV1.2 plasmid was conducted to establish the persistent HBV replication IFNAR-/- mouse model. At last, we applied this model to evaluate the effect of nucleoside analogues entecavir （ETV） on HBV replication. It was found that there was no difference in the serum HBsAg and HBeAg levels and HBcAg expression in the liver tissue between the ETV treated groups and normal saline （NS） treated group, but the serum HBV DNA levels were significantly suppressed 10, 25, 40 and 55 days af- ter the ETV treatment [P=0.035, P=0.00, P=0.149 and P=-0.084, IFNAR knockout （KO） control group vs. C57BL/6 ETV groups, respectively; P=0.081, P=0.001, P=0.243 and P=-0.147, IFNAR KO control group vs. IFNAR KO ETV groups, respectively]. Interestingly, there was no difference in serum HBV DNA levels between the ETV treated IFNAR/- and C57BL/6 mice. This result suggests that HBV sup- pression during ETV treatments doesn＇t depend on type Ⅰinterferon and IFNAR. Collectively, persis- tent HBV replication IFNAR/ mouse model that we established is a useful and convenient tool to detect the function of the type Ⅰ interferon and IFNAR in HBV infection and anti-HBV treatments.
基金grants from Beijing Natural Science Foundation(No.19G10290)National Natural Science Foundation of China(No.81772184).
文摘Enterovirus A71(EV-A71) is the major pathogen responsible for the severe hand, foot and mouth disease worldwide, for which few effective antiviral drugs are presently available. Interferon-a(IFN-a) has been used in antiviral therapy for decades;it has been reported that EV-A71 antagonizes the antiviral activity of IFN-a based on viral 2 Apro-mediated reduction of the interferon-alpha receptor 1(IFNAR1);however, the mechanism remains unknown. Here, we showed a significant increase in IFNAR1 protein induced by IFN-a in RD cells, whereas EV-A71 infection caused obvious downregulation of the IFNAR1 protein and blockage of IFN-a signaling. Subsequently, we observed that EV-A71 2 Apro inhibited IFNAR1 translation by cleavage of the eukaryotic initiation factor 4 GI(eIF4GI), without affecting IFNAR1 m RNA levels induced by IFN-a. The inhibition of IFNAR1 translation also occurred in puromycin-induced apoptotic cells when caspase-3 cleaved e IF4 GI. Importantly, we verified that 2 Aprocould activate cellular caspase-3, which was subsequently involved in e IF4 GI cleavage mediated by 2 Apro. Furthermore, inhibition of caspase-3 activation resulted in the partial restoration of IFNAR1 in cells transfected with 2 A or infected with EV-A71, suggesting the pivotal role of both viral 2 Aproand caspase-3 activation in the disturbance of IFN-a signaling. Collectively, we elucidate a novel mechanism by which cellular caspase-3 contributes to viral 2 Apro-mediated down-regulation of IFNAR1 at the translation level during EV-A71 infection, indicating that caspase-3 inhibition could be a potential complementary strategy to improve clinical anti-EV-A71 therapy with IFN-a.
基金supported by the National Key Research and Development Program of China(2018YFE0107500)the Natural Science Foundation Project of Science and Technology Agency of Chongqing YuZhong District(20200122)to Hu Yuana Natural Science Foundation Project of CQ CSTC(cstc2021jcyj-msxmX0276)to Chen YanMeng
文摘Casein kinase 1α(CK1α) mediates the phosphorylation and degradation of interferon-α/β receptor 1(IFNAR1) in response to viral infection. However, how CK1α regulates hepatitis B virus(HBV) replication and the anti-HBV effects of IFN-α are less reported. Here we show that CK1α can interact with IFNAR1 in hepatoma carcinoma cells and increased the abundance of IFNAR1 by reducing the ubiquitination levels in the presence of HBV.Furthermore, CK1α promotes the IFN-α triggered JAK-STAT signaling pathway and consequently enhances the antiviral effects of IFN-α against HBV replication. Our results collectively provide evidence that CK1α positively regulates the anti-HBV activity of IFN-α in hepatoma carcinoma cells, which would be a promising therapeutic target to improve the effectiveness of IFN-α therapy to cure CHB.
基金supported by the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)the National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘Due to their inability to generate a complete immune response, mice knockout for type I interferon （IFN） receptors （Ifnar-/-） are more susceptible to viral infections, and are thus commonly used for pathogenesis studies. This mouse model has been used to study many diseases caused by highly pathogenic viruses from many families, including the Flaviviridae, Filoviridae, Arenaviridae, Bunyaviridae, Henipaviridae, and Togaviridae. In this review, we summarize the findings from these animal studies, and discuss the pros and cons of using this model versus other known methods for studying pathogenesis in animals.
文摘Genome-wide association analysis allows the identification of potential candidate genes involved in the development of severe coronavirus disease 2019(COVID-19).Hence,it seems that genetics matters here,as well.Nevertheless,the virus's nature,including its RNA structure,determines the rate of mutations leading to new viral strains with all epidemiological and clinical consequences.Given these observations,we herein comment on the current hypotheses about the possible role of the genes in association with COVID-19 severity.We discuss some of the major candidate genes that have been identified as potential genetic factors associated with the COVID-19 severity and infection susceptibility:HLA,ABO,ACE2,TLR7,ApoE,TYK2,OAS,DPP9,IFNAR2,CCR2,etc.Further study of genes and genetic variants will be of great benefit for the prevention and assessment of the individual risk and disease severity in different populations.These scientific data will serve as a basis for the development of clinically applicable diagnostic and prognostic tests for patients at high risk of COVID-19.
基金supported by the National Key Research and Development Program of China(2018YFA0800504)the National Natural Science Foundation of China(31922020)funding provided by Plastech Pharmaceutical Technology Co.,Ltd.
文摘Direct conversion of cardiac fibroblasts(CFs)to cardiomyocytes(CMs)in vivo to regenerate heart tissue is an attractive approach.After myocardial infarction(MI),heart repair proceeds with an inflammation stage initiated by monocytes infiltration of the infarct zone establishing an immune microenvironment.However,whether and how the MI microenvironment influences the reprogramming of CFs remains unclear.Here,we found that in comparison with cardiac fibroblasts(CFs)cultured in vitro,CFs that transplanted into infarct region of MI mouse models resisted to cardiac reprogramming.RNA-seq analysis revealed upregulation of interferon(IFN)response genes in transplanted CFs,and subsequent inhibition of the IFN receptors increased reprogramming efficiency in vivo.Macrophage-secreted IFN-βwas identified as the dominant upstream signaling factor after MI.CFs treated with macrophage-conditioned medium containing IFN-βdisplayed reduced reprogramming efficiency,while macrophage depletion or blocking the IFN signaling pathway after MI increased reprogramming efficiency in vivo.Co-IP,BiFC and Cut-tag assays showed that phosphorylated STAT1 downstream of IFN signaling in CFs could interact with the reprogramming factor GATA4 and inhibit the GATA4 chromatin occupancy in cardiac genes.Furthermore,upregulation of IFN-IFNAR-p-STAT1 signaling could stimulate CFs secretion of CCL2/7/12 chemokines,subsequently recruiting IFN-β-secreting macrophages.Together,these immune cells further activate STAT1 phosphorylation,enhancing CCL2/7/12 secretion and immune cell recruitment,ultimately forming a self-reinforcing positive feedback loop between CFs and macrophages via IFN-IFNAR-p-STAT1 that inhibits cardiac reprogramming in vivo.Cumulatively,our findings uncover an intercellular self-stimulating inflammatory circuit as a microenvironmental molecular barrier of in situ cardiac reprogramming that needs to be overcome for regenerative medicine applications.
基金National Natural Science Foundation of China(31970844,32170927)to SDX.
文摘Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral activity.SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling.Mechanistically,SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8,consequently restricting the interaction between USP8 and IFNAR2.The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation,thus attenuating IFN-I antiviral activity.Correspondingly,the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2,leading to a reduction in IFNAR2 ubiquitination and,consequently,an enhancement in IFN-I-induced signaling.This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.
