STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Her...STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Here,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric mice.In addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral blood.Mechanistically,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)mice.Interestingly,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts.Taken together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.展开更多
Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the cytosol.The released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I i...Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the cytosol.The released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I interferon and other effector genes.These processes contribute to the innate immune response to viral infection and other stress factors.The deregulation of these processes causes autoimmune diseases,inflammatory metabolic disorders and cancer.Therefore,the cGAS-MITA/STING pathway is a potential target for intervention in infectious,inflammatory and autoimmune diseases as well as cancer.In this review,we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway,the effects of the pathway under various physiological and pathological conditions,and advances in the development of drugs that target cGAS and MITA/STING.展开更多
Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The ...Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.展开更多
MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified Z...MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.展开更多
Viral infection induces the initiation of antiviral effectors and cytokines which are critical mediators of innate antiviral responses.The critical molecular determinants are responsible for triggering an appropriate ...Viral infection induces the initiation of antiviral effectors and cytokines which are critical mediators of innate antiviral responses.The critical molecular determinants are responsible for triggering an appropriate immune response.Long noncoding RNAs(lncRNAs)have emerged as new gene modulators involved in various biological processes,while how lncRNAs operate in lower vertebrates are still unknown.Here,we discover a long noncoding RNA,termed antiviral-associated long noncoding RNA(AANCR),as a novel regulator for innate antiviral responses in teleost fish.The results indicate that fish MITA plays an essential role in host antiviral responses and inhibition of Siniperca chuatsi rhabdovirus(SCRV)production.miR-210 reduces MITA expression and suppress MITA-mediated antiviral responses,which may help viruses evade host antiviral responses.Further,AANCR functions as a competing endogenous RNA(ceRNA)for miR-210 to control protein abundance of MITA,thereby inhibiting SCRV replication and promoting antiviral responses.Our data not only shed new light on understanding the function role of lncRNA in biological processes in teleost fish,but confirmed the hypothesis that ceRNA networks exist widely in vertebrates.展开更多
The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses...The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses microbial or mislocated cellular DNA in the cytosol to trigger innate immune responses.cGAS senses cytosolic DNA without a preference of self-or nonself-DNA.How the cGAS-MITA/STING axis is inactivated upon nuclear envelope breakdown(NEBD)at mitotic entry in vertebrate cells to avoid self-DNA sensing remains unclear until very recently.In this review,we summarize the recent advances on how cGAS responds to chromosomes upon NEBD and the mechanisms involved in the inactivation of the cGAS-MITA/STING pathways in mitosis.展开更多
Control of host autophagy acceleration or attenuation has been confirmed in multiple terrestrial animal viruses.Little is known about such mechanisms in aquatic viruses.Here,we report a selective and ingenious autopha...Control of host autophagy acceleration or attenuation has been confirmed in multiple terrestrial animal viruses.Little is known about such mechanisms in aquatic viruses.Here,we report a selective and ingenious autophagy modulation regulated by kinase-like protein(KLP)of cyprinid herpesvirus 2(CyHV2)to restrict interferon(IFN)production by degrading IFN regulatory factor(IRF)3 activation(MITA).First,exogenous DNA and RNAmediated IFN activation were both abrogated by CyHV2 KLP.The common intersection point of MITA with these two signaling pathways was the interaction with KLP.The C terminus of MITA was indispensable for the interaction and was recruited by KLP in subcellular colocalization analysis.Subsequently,we found that KLP degraded MITA in an autophagy-lysosome-dependent manner and,interestingly,individual KLP could not launch host autophagic flow except in the presence of MITA.KLP was also colocalized with the autophagy components Beclin1 and ATG14 and enhanced Beclin1 stability,but not ATG14,through K63-linked polyubiquitination.Finally,KLP significantly decreased the normal state or MITA-enhanced cellular antiviral capacity.These data demonstrated an elaborate autophagic process manipulated by a fish virus only in the presence of the host target,illuminating a mechanism of aquatic viral immune evasion.展开更多
基金supported by grants from the National Key Research and Development Program of China(Grant Nos.2022YFC3401500 and 2023YFC2306100)the Natural Science Foundation of China(Grant Nos.31930040,32070900,82000670,32270951,32200710,and 823B1006)+3 种基金the Fundamental Research Funds for the Central Universities(Grant Nos.2042022kf1187,2042022kf1123 and 2042022dx0003)the Major Scientific and Technological Project of Hubei Province(Grant No.2022ACA005)the Translational Medicine and Interdisciplinary Research Joint Found of Zhongnan Hospital of Wuhan University(Grant.No.ZNJC202218)the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(Grant No.2020PT320-004).
文摘STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Here,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric mice.In addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral blood.Mechanistically,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)mice.Interestingly,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts.Taken together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.
基金supported by grants from the State Key R&D Program of China(2022YFA1304900)the Fundamental Research Funds for the Central Universities(2042022dx0003)+2 种基金the National Natural Science Foundation of China(32188101,31830024)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(Grant No.ZNJC202205).
文摘Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the cytosol.The released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I interferon and other effector genes.These processes contribute to the innate immune response to viral infection and other stress factors.The deregulation of these processes causes autoimmune diseases,inflammatory metabolic disorders and cancer.Therefore,the cGAS-MITA/STING pathway is a potential target for intervention in infectious,inflammatory and autoimmune diseases as well as cancer.In this review,we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway,the effects of the pathway under various physiological and pathological conditions,and advances in the development of drugs that target cGAS and MITA/STING.
基金supported by grants from the State Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024,31922021,31771555,31630045,and 31801188)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.
基金supported by grants from the National Key R&D Program of China(2017YFA0505800,2016YFA0502102)the National Natural Science Foundation of China(31630045,31521091,91429304 and 31671465)+1 种基金the Fundamental Research Funds for the Central Universities(2042017kf0205,2042017kf0242)Wuhan University Experiment Technology Project Funding.
文摘MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.
基金supported by the National Science Foundation for Outstanding Young Scholars(31822057)the National Key Research and Development Project(2018YFD0900503)。
文摘Viral infection induces the initiation of antiviral effectors and cytokines which are critical mediators of innate antiviral responses.The critical molecular determinants are responsible for triggering an appropriate immune response.Long noncoding RNAs(lncRNAs)have emerged as new gene modulators involved in various biological processes,while how lncRNAs operate in lower vertebrates are still unknown.Here,we discover a long noncoding RNA,termed antiviral-associated long noncoding RNA(AANCR),as a novel regulator for innate antiviral responses in teleost fish.The results indicate that fish MITA plays an essential role in host antiviral responses and inhibition of Siniperca chuatsi rhabdovirus(SCRV)production.miR-210 reduces MITA expression and suppress MITA-mediated antiviral responses,which may help viruses evade host antiviral responses.Further,AANCR functions as a competing endogenous RNA(ceRNA)for miR-210 to control protein abundance of MITA,thereby inhibiting SCRV replication and promoting antiviral responses.Our data not only shed new light on understanding the function role of lncRNA in biological processes in teleost fish,but confirmed the hypothesis that ceRNA networks exist widely in vertebrates.
基金supported by grants from the National Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024 and 31630045)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘The cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-mediator of interferon response factor 3 acti-vation/stimulator of interferon genes(MITA/STING)axis has emerged as a major pathway,which senses microbial or mislocated cellular DNA in the cytosol to trigger innate immune responses.cGAS senses cytosolic DNA without a preference of self-or nonself-DNA.How the cGAS-MITA/STING axis is inactivated upon nuclear envelope breakdown(NEBD)at mitotic entry in vertebrate cells to avoid self-DNA sensing remains unclear until very recently.In this review,we summarize the recent advances on how cGAS responds to chromosomes upon NEBD and the mechanisms involved in the inactivation of the cGAS-MITA/STING pathways in mitosis.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA24030203 and XDA24030104)National Key Research and Development Program of China(2018YFD0900504)National Natural Science Foundation of China(32073009)and the Youth Innovation Promotion Association provided funding to Shun Li.National Natural Science Foundation of China provided funding to Long-Feng Lu under grant number 32173023.National Natural Science Foundation of China provided funding to Dan-Dan Chen under grant number 32002431.
文摘Control of host autophagy acceleration or attenuation has been confirmed in multiple terrestrial animal viruses.Little is known about such mechanisms in aquatic viruses.Here,we report a selective and ingenious autophagy modulation regulated by kinase-like protein(KLP)of cyprinid herpesvirus 2(CyHV2)to restrict interferon(IFN)production by degrading IFN regulatory factor(IRF)3 activation(MITA).First,exogenous DNA and RNAmediated IFN activation were both abrogated by CyHV2 KLP.The common intersection point of MITA with these two signaling pathways was the interaction with KLP.The C terminus of MITA was indispensable for the interaction and was recruited by KLP in subcellular colocalization analysis.Subsequently,we found that KLP degraded MITA in an autophagy-lysosome-dependent manner and,interestingly,individual KLP could not launch host autophagic flow except in the presence of MITA.KLP was also colocalized with the autophagy components Beclin1 and ATG14 and enhanced Beclin1 stability,but not ATG14,through K63-linked polyubiquitination.Finally,KLP significantly decreased the normal state or MITA-enhanced cellular antiviral capacity.These data demonstrated an elaborate autophagic process manipulated by a fish virus only in the presence of the host target,illuminating a mechanism of aquatic viral immune evasion.
