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
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
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
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.
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.
