Berberine,a constituent of some traditional Chinese medicinal plants,has been reported to have cytotoxicity effects on different human cancer cell lines.There is no available information about the effects and mechanis...Berberine,a constituent of some traditional Chinese medicinal plants,has been reported to have cytotoxicity effects on different human cancer cell lines.There is no available information about the effects and mechanism of action of berberine on human colon cancer cell line HCT-8.In this paper,the cytotoxicity of berberine on HCT-8 cancer cells was investigated by MTT assay,fluorescence microscopy and flow cytometry analysis.Our data revealed that berberine could significantly inhibit the growth of HCT-8 cells in a dose-and time-dependent manner.Morphology of apoptotic cells was studied with acridine orange/ethidium bromide staining.The concentrations of lactate dehydrogenase and both acid and alkaline phos-phatases were significantly increased in cell supernatants after berberine treatment,suggesting cell death.Furthermore,flow cytometry analysis showed that berberine could arrest HCT-8 cells at S phase in a time-dependent manner.To further investigate the apoptotic molecular mechanism,reverse transcription-poly-merase chain reaction(RT-PCR)and western blotting methods were used.The up-regulated mRNA and/or protein expressions of Fas,FasL,TNF-α,caspase-3 and down-regulation of pro-caspase-3 suggest that the death receptor pathway may be involved in the apoptotic pathway induced by berberine.Decrease of Bcl-2 and increase of Bax in mRNA and/or protein expressions showed that the Bcl-2 family proteins were involved in berberine-induced apoptosis.We also found that berberine-induced apoptosis was associated with an up-regulated expressions of p53 and prohibitin(PHB),and decreased vimentin expression.These results suggest that berberine can suppress cell growth and reduce cell survival by arresting the cell-cycle and by inducing apoptosis of HCT-8 cells.展开更多
Upon DNA virus infection,cGAS senses viral DNA and triggers MITA(also called STING)-dependent induction of type I interferons(IFN-Is)and other cytokines/chemokines.IFN-Is further activate STAT1/2 to induce interferon-...Upon DNA virus infection,cGAS senses viral DNA and triggers MITA(also called STING)-dependent induction of type I interferons(IFN-Is)and other cytokines/chemokines.IFN-Is further activate STAT1/2 to induce interferon-stimulated genes(ISGs)and the innate antiviral response.How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood.In this study,we found that FBXW7,a substrate recognition component of the SCF E3 ubiquitin ligase complex,is a multifaceted regulator of the innate immune response to DNA viruses.In uninfected cells,FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus.This leads to the downregulation of sulfated glycosaminoglycans(sGAGs)in the Golgi apparatus and the inactivation of MITA in uninfected cells.In addition,FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC,which is a repressor of STAT1/2,leading to proper STAT1/2 levels in uninfected cells.The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells.Infection with DNA viruses activates the PI3K-AKT axis,which inactivates GSK3α/βand inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3,leading to increased production of sGAGs,activation of MITA and rapid onset of the innate antiviral response.Consistently,gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells.These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.展开更多
Alloyed based anode materials with high theoretical specific capacity and low reaction potential are considered to be highly potential high-energy density anode materials for alkali metal ion batteries(AMIBs).Thus,the...Alloyed based anode materials with high theoretical specific capacity and low reaction potential are considered to be highly potential high-energy density anode materials for alkali metal ion batteries(AMIBs).Thus,the design of alloyed based materials with high electrochemical performance has attracted great attention.Among the numerous characterization methods for guiding electrode materials design,in situ transmission electron microscopy(TEM)gradually plays an irreplaceable role due to its high temporal and spatial resolution in directly observing the change of morphology,crystal structure and element evolutions.Herein,we reviewed the two current research hotspots and mainly focused on the structure design of alloyed based electrode material under the guidance of in situ TEM.Specifically,various nanostructure designs of alloyed based electrode materials with guidance of in situ TEM were employed to solve the key scientific issues of the violent volume change during alloying/dealloying processes for enhanced electrochemical performances.Mainly through introducing buffer space in the electrode material to reduce volume change to improve structural stability,including porous structure(0 D),nanotube structure(1 D),simple hollow structure,yolk-shell structure and some hybrid hollow structures(3 D).Furthermore,the direct guidance of in situ TEM is expected for creating new opportunities to nextgeneration electrode material design for AMIBs.展开更多
In this research,the performance of regular rapeseed oil(RSO)and modified low-linolenic rapeseed oil(LLRO)during frying was assessed using a frying procedure that commonly found in fast-food restaurants.Key physicoche...In this research,the performance of regular rapeseed oil(RSO)and modified low-linolenic rapeseed oil(LLRO)during frying was assessed using a frying procedure that commonly found in fast-food restaurants.Key physicochemical attributes of these oils were investigated.RSO and LLRO differed for initial linolenic acid(12.21%vs.2.59%),linoleic acid(19.15%vs.24.73%).After 6 successive days frying period of French fries,the ratio of linoleic acid to palmitic acid dropped by 54.49%in RSO,higher than that in LLRO(51.54%).The increment in total oxidation value for LLRO(40.46 unit)was observed to be significantly lower than those of RSO(42.58 unit).The changes in carbonyl group value and iodine value throughout the frying trial were also lower in LLRO compared to RSO.The formation rate in total polar compounds for LLRO was 1.08%per frying day,lower than that of RSO(1.31%).In addition,the formation in color component and degradation in tocopherols were proportional to the frying time for two frying oils.Besides,a longer induction period was also observed in LLRO(8.87 h)compared to RSO(7.68 h)after frying period.Overall,LLRO exhibited the better frying stability,which was confirmed by principal component analysis(PCA).展开更多
The tripartite motif-containing （TRIM） proteins represent the largest E3 ubiquitin Ugase family. The multifaceted roles of TRIM38 in innate immunity and inflammation have been intensively investigated in recent year...The tripartite motif-containing （TRIM） proteins represent the largest E3 ubiquitin Ugase family. The multifaceted roles of TRIM38 in innate immunity and inflammation have been intensively investigated in recent years. TRIM38 is essential for cytosolic RNA or DNA sensor-mediated innate immune responses to both RNA and DNA viruses, while negatively regulating TLR3/4- and TNF/IL-1β-triggered inflammatory responses. In these processes, TRIM38 acts as an E3 ubiquitin or SUMO ligase, which targets key cellular signaling components, or as an enzymatic activity-independent regulator. This review summarizes recent advances that highlight the critical roles of TRIM38 in the reeulation of Droner innate immune and inflammatorv responses.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
Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiv...Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.展开更多
Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of ty...Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.展开更多
Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic.We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice.Progesterone induces...Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic.We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice.Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice,whereas knockout of the progesterone receptor PGR has opposite effects.Mechanistically,stimulation of PGR by progesterone activates the tyrosine kinase SRC,which phosphorylates the transcriptional factor IRF3 at Y107.展开更多
The mitochondrial virus-induced signaling adaptor(VISA,also called mitochondrial antiviral signaling,MAVS)protein is a central adaptor in the innate immune response to cytosolic viral RNA.Viral infection causes the ag...The mitochondrial virus-induced signaling adaptor(VISA,also called mitochondrial antiviral signaling,MAVS)protein is a central adaptor in the innate immune response to cytosolic viral RNA.Viral infection causes the aggregation of VISA,which is important for its recruitment of downstream signaling components.How VISA aggregation is regulated remains unknown.Here,we found that sorting nexin 8(SNX8)is a positive regulator of the RNA virus-triggered induction of downstream effector genes and innate immune response.The brains and lungs of Snx8^(−/−)mice infected with RNA viruses exhibited lower serum cytokine levels and higher viral titers than those of wild-type mice,resulting in higher lethality.Mechanistically,viral infection induced the translocation of SNX8 from the cytosol to mitochondria and its increased association with VISA,leading to VISA aggregation,its recruitment of downstream signaling components and the induction of downstream antiviral genes.Our findings suggest that SNX8 is a critical component of the RIG-I-like receptor(RLR)-mediated innate immune response by modulating VISA aggregation and activation.展开更多
In the version of this article initially published,three unintended errors were made during manuscript preparation.(1)The caption of Fig 4a was incorrect,and the correct statement is‘Effects of SNX8-deficiency on vir...In the version of this article initially published,three unintended errors were made during manuscript preparation.(1)The caption of Fig 4a was incorrect,and the correct statement is‘Effects of SNX8-deficiency on virus-induced death of mice.Mice were infected intraperitoneally(i.p.)with VSV at 5×107 pfu per mouse(n=10 for each genotype)or EMCV at 5×106 pfu per mouse(n=10 for Snx8+/+,n=11 for Snx8−/−).Mouse survival was observed and recorded for 12 days.’(2)Fig 2a and Fig 2e were represented erroneously.The correct Fig 2 is shown below.(3)Typos were found in the description of the qPCR primers for GAPDH and IFNB1 in the Material and Method section,the correct primers are'GAPDH GAGTCAACGGATTTGGTCGT(forward)and GACAAGCTTCCCGTTCTCAG(reverse);IFNB1 TTGTTGAGAACCTC CTGGCT(forward)and TGACTATGGTCCAGGCACAG(reverse)'.The results and conclusions are not affected.展开更多
Hydrogen peroxide(H2O2)detection in biological systems is of significant importance,which act as critical second messenger in fundamental biological processes.Here,we report on a chemoselective fluorescent naphthylimi...Hydrogen peroxide(H2O2)detection in biological systems is of significant importance,which act as critical second messenger in fundamental biological processes.Here,we report on a chemoselective fluorescent naphthylimide peroxide probe(NPP)for the H_(2)O_(2)detection in vitro and in vivo.NPP is a phenylboronic acid-caged chromophore that selectively responds to H_(2)O_(2)through a selfimmolate mechanism.NPP exhibited high sensitivity and selectivity to H_(2)O_(2)with distinctive fluorescence change due to the excellent two-photon excitation property,which permits the facile detection of inflammation produced H_(2)O_(2)and offers chance to monitor the inflammatory stages in diseased cells.展开更多
基金the Excellent Young Scientist funds(number 2006J23JH024)of the Science and Technology Foundation of Dalian,Chinathe First Special China Post-Doctor Foundation(number 200801397)the Academic Scholarship for Doc-toral Candidates of Ministry of Education.
文摘Berberine,a constituent of some traditional Chinese medicinal plants,has been reported to have cytotoxicity effects on different human cancer cell lines.There is no available information about the effects and mechanism of action of berberine on human colon cancer cell line HCT-8.In this paper,the cytotoxicity of berberine on HCT-8 cancer cells was investigated by MTT assay,fluorescence microscopy and flow cytometry analysis.Our data revealed that berberine could significantly inhibit the growth of HCT-8 cells in a dose-and time-dependent manner.Morphology of apoptotic cells was studied with acridine orange/ethidium bromide staining.The concentrations of lactate dehydrogenase and both acid and alkaline phos-phatases were significantly increased in cell supernatants after berberine treatment,suggesting cell death.Furthermore,flow cytometry analysis showed that berberine could arrest HCT-8 cells at S phase in a time-dependent manner.To further investigate the apoptotic molecular mechanism,reverse transcription-poly-merase chain reaction(RT-PCR)and western blotting methods were used.The up-regulated mRNA and/or protein expressions of Fas,FasL,TNF-α,caspase-3 and down-regulation of pro-caspase-3 suggest that the death receptor pathway may be involved in the apoptotic pathway induced by berberine.Decrease of Bcl-2 and increase of Bax in mRNA and/or protein expressions showed that the Bcl-2 family proteins were involved in berberine-induced apoptosis.We also found that berberine-induced apoptosis was associated with an up-regulated expressions of p53 and prohibitin(PHB),and decreased vimentin expression.These results suggest that berberine can suppress cell growth and reduce cell survival by arresting the cell-cycle and by inducing apoptosis of HCT-8 cells.
基金supported by grants from the State Key R&D Program of China(2022YFA1304900 and 2021YFA1302400)the Major Project of Guangzhou National Laboratory(GZNL2024A01016)+3 种基金the National Natural Science Foundation of China(32188101,32470760 and 32170713 and 82404775)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the Fundamental Research Funds for the Central Universities(2042022dx0003,2042025kf0038)the Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(Grant No.ZNJC202205).
文摘Upon DNA virus infection,cGAS senses viral DNA and triggers MITA(also called STING)-dependent induction of type I interferons(IFN-Is)and other cytokines/chemokines.IFN-Is further activate STAT1/2 to induce interferon-stimulated genes(ISGs)and the innate antiviral response.How the innate antiviral response is silenced in uninfected cells and efficiently mounts upon viral infection is not fully understood.In this study,we found that FBXW7,a substrate recognition component of the SCF E3 ubiquitin ligase complex,is a multifaceted regulator of the innate immune response to DNA viruses.In uninfected cells,FBXW7 mediates the polyubiquitination and degradation of GSK3α/β-phosphorylated SLC35B2/3 at the Golgi apparatus.This leads to the downregulation of sulfated glycosaminoglycans(sGAGs)in the Golgi apparatus and the inactivation of MITA in uninfected cells.In addition,FBXW7 mediates the degradation of GSK3α/β-phosphorylated MYC,which is a repressor of STAT1/2,leading to proper STAT1/2 levels in uninfected cells.The differential regulation of FBXW7 on MITA and STAT1/2 ensures inactivation but is ready for fast mount of the innate immune response in uninfected cells.Infection with DNA viruses activates the PI3K-AKT axis,which inactivates GSK3α/βand inhibits FBXW7-mediated polyubiquitination and degradation of SLC35B2/3,leading to increased production of sGAGs,activation of MITA and rapid onset of the innate antiviral response.Consistently,gene disruption experiments indicate that FBXW7 modulates the innate antiviral response in human THP-1 and mouse BMDM cells.These findings suggest that FBXW7 functions as a versatile regulator of the innate immune response to DNA viruses by differentially regulating upstream and downstream components of the type I interferon induction loop.
基金supported by the National Natural Science Foundation of China(No.51621001)the National Key Research and Development Program of China(No.2016YFA0202604)Key Laboratory of Resource Chemistry,Ministry of Education Joint International Research Laboratory of Resource Chemistry and the open fund from Hunan Provincial Key Laboratory of Advanced Materials for New Energy Storage and Conversion(No.2018TP1037-202005)。
文摘Alloyed based anode materials with high theoretical specific capacity and low reaction potential are considered to be highly potential high-energy density anode materials for alkali metal ion batteries(AMIBs).Thus,the design of alloyed based materials with high electrochemical performance has attracted great attention.Among the numerous characterization methods for guiding electrode materials design,in situ transmission electron microscopy(TEM)gradually plays an irreplaceable role due to its high temporal and spatial resolution in directly observing the change of morphology,crystal structure and element evolutions.Herein,we reviewed the two current research hotspots and mainly focused on the structure design of alloyed based electrode material under the guidance of in situ TEM.Specifically,various nanostructure designs of alloyed based electrode materials with guidance of in situ TEM were employed to solve the key scientific issues of the violent volume change during alloying/dealloying processes for enhanced electrochemical performances.Mainly through introducing buffer space in the electrode material to reduce volume change to improve structural stability,including porous structure(0 D),nanotube structure(1 D),simple hollow structure,yolk-shell structure and some hybrid hollow structures(3 D).Furthermore,the direct guidance of in situ TEM is expected for creating new opportunities to nextgeneration electrode material design for AMIBs.
基金This work was financially supported by the Science and Technology Research Project of Jiangxi Provincial Education Department(GJJ210322)the National Natural Science Foundation of China(No.32260635).
文摘In this research,the performance of regular rapeseed oil(RSO)and modified low-linolenic rapeseed oil(LLRO)during frying was assessed using a frying procedure that commonly found in fast-food restaurants.Key physicochemical attributes of these oils were investigated.RSO and LLRO differed for initial linolenic acid(12.21%vs.2.59%),linoleic acid(19.15%vs.24.73%).After 6 successive days frying period of French fries,the ratio of linoleic acid to palmitic acid dropped by 54.49%in RSO,higher than that in LLRO(51.54%).The increment in total oxidation value for LLRO(40.46 unit)was observed to be significantly lower than those of RSO(42.58 unit).The changes in carbonyl group value and iodine value throughout the frying trial were also lower in LLRO compared to RSO.The formation rate in total polar compounds for LLRO was 1.08%per frying day,lower than that of RSO(1.31%).In addition,the formation in color component and degradation in tocopherols were proportional to the frying time for two frying oils.Besides,a longer induction period was also observed in LLRO(8.87 h)compared to RSO(7.68 h)after frying period.Overall,LLRO exhibited the better frying stability,which was confirmed by principal component analysis(PCA).
基金We thank members of the Shu laboratory for helpful discussions. The work in the authors＇ laboratory is supported by grants from the Ministry of Science and Technology of China （2016YFA0502102, 2014CB910103）, the National Natural Science Foundation of China （3163000013, 31521091, and 91429304） and National Postdoctoral Program for Innovative Talents （BX201600116）.
文摘The tripartite motif-containing （TRIM） proteins represent the largest E3 ubiquitin Ugase family. The multifaceted roles of TRIM38 in innate immunity and inflammation have been intensively investigated in recent years. TRIM38 is essential for cytosolic RNA or DNA sensor-mediated innate immune responses to both RNA and DNA viruses, while negatively regulating TLR3/4- and TNF/IL-1β-triggered inflammatory responses. In these processes, TRIM38 acts as an E3 ubiquitin or SUMO ligase, which targets key cellular signaling components, or as an enzymatic activity-independent regulator. This review summarizes recent advances that highlight the critical roles of TRIM38 in the reeulation of Droner innate immune and inflammatorv responses.
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 grants from the National Natural Science Foundation of China(32188101,31830024,31922021 and 32170713)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Upon viral infection, cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS- or MITA/STING-mediated innate antiviral response. Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear. Here, we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2. We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner. Mechanistically, epinephrine/norepinephrine stimulation activated the downstream kinase PKA, which catalyzed the phosphorylation of MITA at S241, S243 and T263, inhibiting MITA activation and suppressing the innate immune response to DNA virus. In addition, phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus. These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.
基金This work was supported by grants from the State Key R&D Program of China(2022YFA1304900)the National Natural Science Foundation of China(32188101,31830024,31922021,and 32170713)+1 种基金the Fundamental Research Funds for the Central Universities(2042022dx0003)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2019-/2M-5-071).
文摘Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast cancers.How ERαdrives breast carcinogenesis is not fully understood.In this study,we show that ERαis a negative regulator of type I interferon(IFN)response.Activation of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite effects.Mechanistically,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 complex.These two events mutually lead to the inhibition of ISG transcription induced by type I IFNs.In a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor growth.Consistently,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival rates.Taken together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.
基金This work was supported by grants from the State Key R&D Program of China(2017YFA0505800 and 2021YFA1302400)the National Natural Science Foundation of China(31922021,32170713,31830042,and 31771555)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Whether and how innate antiviral response is regulated by humoral metabolism remains enigmatic.We show that viral infection induces progesterone via the hypothalamic-pituitary-adrenal axis in mice.Progesterone induces downstream antiviral genes and promotes innate antiviral response in cells and mice,whereas knockout of the progesterone receptor PGR has opposite effects.Mechanistically,stimulation of PGR by progesterone activates the tyrosine kinase SRC,which phosphorylates the transcriptional factor IRF3 at Y107.
基金supported by grants from the State Key R&D Program of China(2017YFA0505800,2016YFA0502102)the National Natural Science Foundation of China(31830024,31800728,31630045,31521091,31671465,and 31771555).
文摘The mitochondrial virus-induced signaling adaptor(VISA,also called mitochondrial antiviral signaling,MAVS)protein is a central adaptor in the innate immune response to cytosolic viral RNA.Viral infection causes the aggregation of VISA,which is important for its recruitment of downstream signaling components.How VISA aggregation is regulated remains unknown.Here,we found that sorting nexin 8(SNX8)is a positive regulator of the RNA virus-triggered induction of downstream effector genes and innate immune response.The brains and lungs of Snx8^(−/−)mice infected with RNA viruses exhibited lower serum cytokine levels and higher viral titers than those of wild-type mice,resulting in higher lethality.Mechanistically,viral infection induced the translocation of SNX8 from the cytosol to mitochondria and its increased association with VISA,leading to VISA aggregation,its recruitment of downstream signaling components and the induction of downstream antiviral genes.Our findings suggest that SNX8 is a critical component of the RIG-I-like receptor(RLR)-mediated innate immune response by modulating VISA aggregation and activation.
文摘In the version of this article initially published,three unintended errors were made during manuscript preparation.(1)The caption of Fig 4a was incorrect,and the correct statement is‘Effects of SNX8-deficiency on virus-induced death of mice.Mice were infected intraperitoneally(i.p.)with VSV at 5×107 pfu per mouse(n=10 for each genotype)or EMCV at 5×106 pfu per mouse(n=10 for Snx8+/+,n=11 for Snx8−/−).Mouse survival was observed and recorded for 12 days.’(2)Fig 2a and Fig 2e were represented erroneously.The correct Fig 2 is shown below.(3)Typos were found in the description of the qPCR primers for GAPDH and IFNB1 in the Material and Method section,the correct primers are'GAPDH GAGTCAACGGATTTGGTCGT(forward)and GACAAGCTTCCCGTTCTCAG(reverse);IFNB1 TTGTTGAGAACCTC CTGGCT(forward)and TGACTATGGTCCAGGCACAG(reverse)'.The results and conclusions are not affected.
基金This work was supported by the National Natural Science Foundation of China(21474077,51233003 and 51533006)the Fundamental Research Funds for the Central Universities.
文摘Hydrogen peroxide(H2O2)detection in biological systems is of significant importance,which act as critical second messenger in fundamental biological processes.Here,we report on a chemoselective fluorescent naphthylimide peroxide probe(NPP)for the H_(2)O_(2)detection in vitro and in vivo.NPP is a phenylboronic acid-caged chromophore that selectively responds to H_(2)O_(2)through a selfimmolate mechanism.NPP exhibited high sensitivity and selectivity to H_(2)O_(2)with distinctive fluorescence change due to the excellent two-photon excitation property,which permits the facile detection of inflammation produced H_(2)O_(2)and offers chance to monitor the inflammatory stages in diseased cells.
