In mammals,mitofusin 2(MFN2)is involved in mitochondrial fusion,and suppresses the virus-induced RIG-I-like receptor(RLR)signaling pathway.However,little is known about the function of MFN2 in non-mammalian species.In...In mammals,mitofusin 2(MFN2)is involved in mitochondrial fusion,and suppresses the virus-induced RIG-I-like receptor(RLR)signaling pathway.However,little is known about the function of MFN2 in non-mammalian species.In the present study,we cloned an MFN2 ortholog(LcMFN2)in large yellow croaker(Larimichthys crocea).Phylogenetic analysis showed that MFN2 emerged after the divergence of amphioxus and vertebrates.The protein sequences of MFN2 were well conserved from fsh to mammals.LcMFN2 was expressed in all the tissues/organs examined at diferent levels,and its expression was upregulated in response to poly(I:C)stimulation.Overexpression of LcMFN2 inhibited MAVS-induced type I interferon(IFN)promoter activation and antiviral gene expression.In contrast,knockdown of endogenous LcMFN2 enhanced poly(I:C)induced production of type I IFNs.Additionally,LcMFN2 enhanced K48-linked polyubiquitination of MAVS,promoting its degradation.Also,overexpression of LcMFN2 impaired the cellular antiviral response,as evidenced by the increased expression of viral genes and more severe cytopathic efects(CPE)in cells infected with spring viremia of carp virus(SVCV).These results indicated that LcMFN2 inhibited type I IFN response by degrading MAVS,suggesting its negative regulatory role in cellular antiviral response.Therefore,our study sheds a new light on the regulatory mechanisms of the cellular antiviral response in teleosts.展开更多
Interferon (IFN) is thought to play an important role in the vertebrate immune system, but systemic knowledge of IFN evolution has yet to be elucidated. To evaluate the phylogenic distribution and evolutionary history...Interferon (IFN) is thought to play an important role in the vertebrate immune system, but systemic knowledge of IFN evolution has yet to be elucidated. To evaluate the phylogenic distribution and evolutionary history of type I IFNs, 13genomes were searched using BLASTn program, and a phylogenetic tree of vertebrate type I IFNs was constructed. In the present study, an IFNδ-like gene in the human genome was identified, refuting the concept that humans have no IFNδ genes, and other mammalian IFN genes were also identified. In the phylogenetic tree, the mammalian IFNβ, IFNɛ, and IFNκ formed a clade separate from the other mammalian type I IFNs, while piscine and avian IFNs formed distinct clades. Based on this phylogenetic analysis and the various characteristics of type I IFNs, the evolutionary history of type I IFNs was further evaluated. Our data indicate that an ancestral IFNα-like gene forms a core from which new IFNs divided during vertebrate evolution. In addition, the data suggest how the other type I IFNs evolved from IFNα and shaped the complex type I IFN system. The promoters of type I IFNs were conserved among different mammals, as well as their genic regions. However, the intergenic regions of type I IFN clusters were not conserved among different mammals, demonstrating a high selection pressure upon type I IFNs during their evolution.展开更多
Background and Aims:Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus(HBV),and is seen as a serious global health problem.HBV infection induces the expression of type I interferon(IF...Background and Aims:Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus(HBV),and is seen as a serious global health problem.HBV infection induces the expression of type I interferon(IFN),including IFN-αand IFN-β,which have anti-HBV activities,and have been used for HBV treatment.IL2-inducible T-cell kinase(ITK)is a tyrosine kinase,which regulates T-cell differentiation and activation,while its precise effects on type I IFN production during HBV infection remain unknown.Methods:We monitored the ITK expression in peripheral blood mononuclear cells(PBMCs)from healthy donors and patients with acute and chronic HBV infection.We used ITK inhibitor ibrutinib to treat hepatocytes and evaluated the type I IFN expression after HBV infection.We also administrated ibrutinib to mice and evaluated its effect on HBV infection in vivo.We generated ITK,suppressor of cytokine signaling 1(SOCS1)knockout and ITK/SOCS1 double knockout cells using CRISPR,and monitored the HBV-induced type I IFN production.Results:ITK and type I IFN were upregulated in patients with acute HBV infection.Inhibition of ITK by ibrutinib suppressed HBVinduced expression of type I IFN mRNA in mice.ITK knockout cells had decreased IRF3 activation but promoted the expression of SOCS1.ITK negatively regulated SOSC1 expression.The down regulation of type I IFN in ITK knockout cells after HBV stimulation was abolished in the absence of SOCS1.Conclusions:ITK regulated HBV-induced expression of type I IFN mRNA by modulating SOCS1.展开更多
DNA sensing and timely activation of interferon(IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells.However,overactivation of immune responses may...DNA sensing and timely activation of interferon(IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells.However,overactivation of immune responses may lead to tissue damage and autoimmune diseases;therefore,these processes must be intricately regulated.STING is the key adaptor protein,which is activated by cyclic GMP-AMP,the second messenger derived from cGAS-mediated DNA sensing.Here,we report that CCDC50,a newly identified autophagy receptor,tunes STING-directed type I IFN signaling activity by delivering K63-polyubiquitinated STING to autolysosomes for degradation.Knockout of CCDC50 significantly increases herpes simplex virus 1(HSV-1)-or DNA ligand-induced production of type I IFN and proinflammatory cytokines.Ccdc50-deficient mice show increased production of IFN,decreased viral replication,reduced cell infiltration,and improved survival rates compared with their wild-type littermates when challenged with HSV-1.Remarkably,the expression of CCDC50 is downregulated in systemic lupus erythematosus(SLE),a chronic autoimmune disease.CCDC50 levels are negatively correlated with IFN signaling pathway activation and disease severity in human SLE patients.CCDC50 deficiency potentiates the cGAS-STING-mediated immune response triggered by SLE serum.Thus,our findings reveal the critical role of CCDC50 in the immune regulation of viral infections and autoimmune diseases and provide insights into the therapeutic implications of CCDC50 manipulation.展开更多
Extracellular DNA is secreted from various sources including apoptotic cells,NETotic neutrophils and bacterial biofilms.Extracellular DNA can stimulate innate immune responses to induce type-I IFN production after bei...Extracellular DNA is secreted from various sources including apoptotic cells,NETotic neutrophils and bacterial biofilms.Extracellular DNA can stimulate innate immune responses to induce type-I IFN production after being endocytosed.This process is central in antiviral responses but it also plays important role in the pathogenesis of a range of autoimmune diseases such as systemic lupus erythematosus.We discuss the recent advances in the understanding of the role of extracellular DNA,released from apoptotic and NETotic cells,in autoimmunity.展开更多
As the first line of immune defense for Mycobacterium tuberculosis （Mtb）, macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant ...As the first line of immune defense for Mycobacterium tuberculosis （Mtb）, macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors （TLRs） expressed on macrophages can recognize pathopatterns （PAMPs） on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor （TNF） and type I Interferons （IFNs）. In addition, Vitamin D receptor （VDR） and Vitamin D-1- hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune respon- ses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes cur- rent knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.展开更多
During human immunodeficiency virus(HIV) infection, type I interferon(IFN-I) signaling induces an antiviral state that includes the production of restriction factors that inhibit virus replication, thereby limiting th...During human immunodeficiency virus(HIV) infection, type I interferon(IFN-I) signaling induces an antiviral state that includes the production of restriction factors that inhibit virus replication, thereby limiting the infection. As seen in other viral infections, type I IFN can also increase systemic immune activation which, in HIV disease, is one of the strongest predictors of disease progression to acquired immune deficiency syndrome(AIDS) and non-AIDS morbidity and mortality.Moreover, IFN-I is associated with CD4 T cell depletion and attenuation of antigen-specific T cell responses. Therefore,therapeutic manipulation of IFN-I signaling to improve HIV disease outcome is a source of much interest and debate in thefield. Recent studies have highlighted the importance of timing(acute vs. chronic infection) and have suggested that specific targeting of type I IFNs and their subtypes may help harness the beneficial roles of the IFN-I system while avoiding its deleterious activities.展开更多
基金This work was supported by National Key Research and Development Program of China under Grant No.2022YFD2401001National Natural Science Foundation of China under Grant No.U1905204+2 种基金China Agriculture Research System of MOF and MARA under Grant No.CARS-47Fujian Science and Technology Department under Grant No.2021N5008Institute of Oceanology of Fuzhou(2021F02).
文摘In mammals,mitofusin 2(MFN2)is involved in mitochondrial fusion,and suppresses the virus-induced RIG-I-like receptor(RLR)signaling pathway.However,little is known about the function of MFN2 in non-mammalian species.In the present study,we cloned an MFN2 ortholog(LcMFN2)in large yellow croaker(Larimichthys crocea).Phylogenetic analysis showed that MFN2 emerged after the divergence of amphioxus and vertebrates.The protein sequences of MFN2 were well conserved from fsh to mammals.LcMFN2 was expressed in all the tissues/organs examined at diferent levels,and its expression was upregulated in response to poly(I:C)stimulation.Overexpression of LcMFN2 inhibited MAVS-induced type I interferon(IFN)promoter activation and antiviral gene expression.In contrast,knockdown of endogenous LcMFN2 enhanced poly(I:C)induced production of type I IFNs.Additionally,LcMFN2 enhanced K48-linked polyubiquitination of MAVS,promoting its degradation.Also,overexpression of LcMFN2 impaired the cellular antiviral response,as evidenced by the increased expression of viral genes and more severe cytopathic efects(CPE)in cells infected with spring viremia of carp virus(SVCV).These results indicated that LcMFN2 inhibited type I IFN response by degrading MAVS,suggesting its negative regulatory role in cellular antiviral response.Therefore,our study sheds a new light on the regulatory mechanisms of the cellular antiviral response in teleosts.
基金funded by the National Natural Science Foundation of China(Grant No.31100644)the Ministry of Science and Technology program of China(Grant Nos.2011AA10A215,and 2010GB24910698).
文摘Interferon (IFN) is thought to play an important role in the vertebrate immune system, but systemic knowledge of IFN evolution has yet to be elucidated. To evaluate the phylogenic distribution and evolutionary history of type I IFNs, 13genomes were searched using BLASTn program, and a phylogenetic tree of vertebrate type I IFNs was constructed. In the present study, an IFNδ-like gene in the human genome was identified, refuting the concept that humans have no IFNδ genes, and other mammalian IFN genes were also identified. In the phylogenetic tree, the mammalian IFNβ, IFNɛ, and IFNκ formed a clade separate from the other mammalian type I IFNs, while piscine and avian IFNs formed distinct clades. Based on this phylogenetic analysis and the various characteristics of type I IFNs, the evolutionary history of type I IFNs was further evaluated. Our data indicate that an ancestral IFNα-like gene forms a core from which new IFNs divided during vertebrate evolution. In addition, the data suggest how the other type I IFNs evolved from IFNα and shaped the complex type I IFN system. The promoters of type I IFNs were conserved among different mammals, as well as their genic regions. However, the intergenic regions of type I IFN clusters were not conserved among different mammals, demonstrating a high selection pressure upon type I IFNs during their evolution.
基金This work was supported by Quanzhou City Science&Technology Program of China(2022NS056).
文摘Background and Aims:Hepatitis B is a vaccine-preventable liver infection caused by the hepatitis B virus(HBV),and is seen as a serious global health problem.HBV infection induces the expression of type I interferon(IFN),including IFN-αand IFN-β,which have anti-HBV activities,and have been used for HBV treatment.IL2-inducible T-cell kinase(ITK)is a tyrosine kinase,which regulates T-cell differentiation and activation,while its precise effects on type I IFN production during HBV infection remain unknown.Methods:We monitored the ITK expression in peripheral blood mononuclear cells(PBMCs)from healthy donors and patients with acute and chronic HBV infection.We used ITK inhibitor ibrutinib to treat hepatocytes and evaluated the type I IFN expression after HBV infection.We also administrated ibrutinib to mice and evaluated its effect on HBV infection in vivo.We generated ITK,suppressor of cytokine signaling 1(SOCS1)knockout and ITK/SOCS1 double knockout cells using CRISPR,and monitored the HBV-induced type I IFN production.Results:ITK and type I IFN were upregulated in patients with acute HBV infection.Inhibition of ITK by ibrutinib suppressed HBVinduced expression of type I IFN mRNA in mice.ITK knockout cells had decreased IRF3 activation but promoted the expression of SOCS1.ITK negatively regulated SOSC1 expression.The down regulation of type I IFN in ITK knockout cells after HBV stimulation was abolished in the absence of SOCS1.Conclusions:ITK regulated HBV-induced expression of type I IFN mRNA by modulating SOCS1.
基金This study is supported by the National Natural Science Foundation of China(#81620108020 to DG and#81801574 to PH)Guangdong Province"Pearl River Talent Plan"Innovation and Entrepreneurship Team Project(2019ZT08Y464 to CL)+1 种基金Shenzhen Science and Technology Program(#JCYJ20200109142201695 and#KQTD20180411143323605 to DG and#JCYJ20190807161415336 to PH)DG is also supported by the Guangdong Zhujiang Talents Programme and the National Ten-thousand Talents Programme.
文摘DNA sensing and timely activation of interferon(IFN)-mediated innate immunity are crucial for the defense against DNA virus infections and the clearance of abnormal cells.However,overactivation of immune responses may lead to tissue damage and autoimmune diseases;therefore,these processes must be intricately regulated.STING is the key adaptor protein,which is activated by cyclic GMP-AMP,the second messenger derived from cGAS-mediated DNA sensing.Here,we report that CCDC50,a newly identified autophagy receptor,tunes STING-directed type I IFN signaling activity by delivering K63-polyubiquitinated STING to autolysosomes for degradation.Knockout of CCDC50 significantly increases herpes simplex virus 1(HSV-1)-or DNA ligand-induced production of type I IFN and proinflammatory cytokines.Ccdc50-deficient mice show increased production of IFN,decreased viral replication,reduced cell infiltration,and improved survival rates compared with their wild-type littermates when challenged with HSV-1.Remarkably,the expression of CCDC50 is downregulated in systemic lupus erythematosus(SLE),a chronic autoimmune disease.CCDC50 levels are negatively correlated with IFN signaling pathway activation and disease severity in human SLE patients.CCDC50 deficiency potentiates the cGAS-STING-mediated immune response triggered by SLE serum.Thus,our findings reveal the critical role of CCDC50 in the immune regulation of viral infections and autoimmune diseases and provide insights into the therapeutic implications of CCDC50 manipulation.
基金funded by Prof Gavin Screaton supported by Wellcome Trust(G.R.S).
文摘Extracellular DNA is secreted from various sources including apoptotic cells,NETotic neutrophils and bacterial biofilms.Extracellular DNA can stimulate innate immune responses to induce type-I IFN production after being endocytosed.This process is central in antiviral responses but it also plays important role in the pathogenesis of a range of autoimmune diseases such as systemic lupus erythematosus.We discuss the recent advances in the understanding of the role of extracellular DNA,released from apoptotic and NETotic cells,in autoimmunity.
文摘As the first line of immune defense for Mycobacterium tuberculosis （Mtb）, macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors （TLRs） expressed on macrophages can recognize pathopatterns （PAMPs） on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor （TNF） and type I Interferons （IFNs）. In addition, Vitamin D receptor （VDR） and Vitamin D-1- hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune respon- ses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes cur- rent knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.
文摘During human immunodeficiency virus(HIV) infection, type I interferon(IFN-I) signaling induces an antiviral state that includes the production of restriction factors that inhibit virus replication, thereby limiting the infection. As seen in other viral infections, type I IFN can also increase systemic immune activation which, in HIV disease, is one of the strongest predictors of disease progression to acquired immune deficiency syndrome(AIDS) and non-AIDS morbidity and mortality.Moreover, IFN-I is associated with CD4 T cell depletion and attenuation of antigen-specific T cell responses. Therefore,therapeutic manipulation of IFN-I signaling to improve HIV disease outcome is a source of much interest and debate in thefield. Recent studies have highlighted the importance of timing(acute vs. chronic infection) and have suggested that specific targeting of type I IFNs and their subtypes may help harness the beneficial roles of the IFN-I system while avoiding its deleterious activities.
