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cGAS-STING pathway in senescence-related inflammation

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National Science Review 2018年第3期5卷 308-310页

作者： Kun Chen Juan Liu Xuetao Cao National Key Laboratory of Medical Molecular Biology Department of Immunology & Center for Immunotherapy Institute of Basic Medical Sciences Peking Union Medical College Chinese Academy of Medical Sciences National Key Laboratory of Medical immunology & Institute of immunology Second Military Medical University

Cellular senescence marked with persistent cell cycle arrest plays critical roles in orchestrating tissue remodeling and immune surveillance in response to multiple developmental and physiological ***,chronic or persistent cellular senescence can promote aberrant inflammatory responses,therefore is linked with variable pathogeneses such as fibrosis,cancer,autoimmune diseases,

关键词： GAS cGAS-STING pathway in senescence-related inflammation

Metabolic control of T-cell immunity via epigenetic mechanisms

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Cellular & Molecular immunology 2018年第3期15卷 203-205页

作者： Xiaomin Zhang Juan Liu Xuetao Cao National Key Laboratory of Medical immunology&Institute of immunology Second Military Medical UniversityShanghai200433China Department of immunology and center for immunotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesBeijing100005China

Metabolism has been increasingly considered to play an important role in inflammation and immunity via modulating cellular signaling and transcriptional networks.1 Dysregulation of metabolic enzymes or mediators is increasingly linked to clinical diseases,such as type I diabetes,gliomas and breast cancer.2,3 Numerous metabolic sensors,such as AMP-mediated protein kinase,mammalian target of rapamycin complex1 and hypoxia-induced factor 1α(HIF-1α),have been shown to regulate immunological responses,such as T-cell activation and macrophage polarization,via modulating the property and activity of signaling pathways.4,5 Moreover,emerging evidence suggests that intermediates from multiple metabolic pathways are important in orchestrating transcriptional and epigenetic *** interaction between metabolic and epigenetic pathways is crucial for coordinating cellular immunological events in response to extracellular stimuli,such as infection,injury and stress,leading to varied biological and pathological outcomes.

关键词： immunity epigenetic inflammation

Engineering bionic T cells: signal 1, signal 2, signal 3, reprogramming and the removal of inhibitory mechanisms

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Cellular & Molecular immunology 2020年第6期17卷 576-586页

作者： Iñaki Etxeberria Irene Olivera Elixabet Bolaños Asunta Cirella Álvaro Teijeira Pedro Berraondo Ignacio Melero Program of immunology and immunotherapy Center for Applied Medical Research(CIMA)PamplonaSpain Navarra Institute for Health Research(IDISNA) PamplonaSpain Centro de Investigación Biomédica en Red de Cáncer(CIBERONC) MadridSpain Department of immunology and immunotherapy Clínica Universidad de NavarraPamplonaSpain

Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy(ACT).The provision of proper costimulatory receptor activity and cytokine stimuli,along with the repression of inhibitory mechanisms,will conceivably make the most of these treatment *** this sense,T cells can be genetically manipulated to become refractory to suppressive mechanisms and exhaustion,last longer and differentiate into memory T cells while endowed with the ability to traffic to malignant *** antitumor effects can be dramatically augmented with permanent or transient gene transfer maneuvers to express or delete/repress genes.A combination of such interventions seeks the creation of the ultimate bionic T cell,perfected to seek and destroy cancer cells upon systemic or local intratumor delivery.

关键词： Adoptive cell therapy T cell engineering Cancer immunotherapy

The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1–IRF3 signaling

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Cellular & Molecular immunology 2019年第10期16卷 800-809页

作者： Hua Zhang Chaofeng Han Tianliang Li Nan Li Xuetao Cao National Key Laboratory of Medical immunology&Institute of immunology Second Military Medical UniversityShanghai 200433China Department of immunology&center for immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

Protein arginine methyltransferases(PRMTs)play diverse biological roles and are specifically involved in immune cell development and ***,their role in antiviral innate immunity has not been *** infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon,which mediates antiviral *** performed a functional screen of the nine mammalian PRMTs for regulators of IFN-βexpression and found that PRMT6 inhibits the antiviral innate immune *** infection also upregulated PRMT6 protein *** generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate ***6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon ***,viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1;this mechanism was independent of PRMT6 methyltransferase ***,PRMT6 inhibits antiviral innate immunity by sequestering IRF3,thereby blocking TBK1-IRF3 *** work demonstrates a methyltransferase-independent role for *** also identifies a negative regulator of the antiviral immune response,which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.

关键词： PRMT6 TBK1 IRF3 IFN antiviral innate immunity

Intracellular HSP70L1 inhibits human dendritic cell maturation by promoting suppressive H3K27me3 and H2AK119Ub1 histone modifications

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Cellular & Molecular immunology 2020年第1期17卷 85-94页

作者： Lin Yi Zhiqing Li Tianju Hu Juan Liu Nan Li Xuetao Cao Shuxun Liu National Key Laboratory of Medical immunology&Institute of immunology Second Military Medical University200433ShanghaiChina Department of immunology&center for immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina

Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and ***,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly *** previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains ***,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular *** stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic ***,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 ***,intracellular HSP70L1 is an inhibitor of human DC *** results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.

关键词： HSP70L1 DNAJC2 Monocyte-derived dendritic cell Histone modification H3K27me3 H2AK119Ub1 H3K4me3

RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis

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Signal Transduction and Targeted Therapy 2022年第8期7卷 3032-3044页

作者： Ha Zhu Kun Chen Yali Chen Juan Liu Xiaomin Zhang Yumei Zhou Qiuyan Liu Bingjing Wang Taoyong Chen Xuetao Cao National Key Laboratory of Medical immunology Institute of ImmunologySecond Military Medical University200433 ShanghaiChina Department of immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina Frontier Research center for Cell Response Institute of ImmunologyCollege of Life SciencesNankai University310071 TianjinChina

RNA-binding proteins(RBPs)play important roles in cancer development and ***,the tumor-promoting RBPs and their partners,which may potentially serve as the cancer therapeutic targets,need to be further ***,we report that zinc finger CCHC domain-containing protein 4(ZCCHC4)is of aberrantly high expression in multiple human cancer tissues and is associated with poor prognosis and chemoresistance in patients of hepatocellular carcinoma(HCC),pancreatic cancer and colon ***4 promotes chemoresistance of HCC cells to DNA-damage agent(DDA)both in vitro and in *** cell deficiency of ZCCHC4 reduces tumor growth in vivo and intratumoral interference of ZCCHC4 expression obviously enhances the DDAinduced antitumor ***,ZCCHC4 inhibits DNA-damage-induced apoptosis in HCC cells by interacting with a new long noncoding RNA(lncRNA)AL133467.2 to hamper its pro-apoptotic ***,ZCCHC4 blocks the interaction between AL133467.2 andγH2AX upon DDA treatment to inhibit apoptotic signaling and promote chemoresistance to *** of ZCCHC4 promotes AL133467.2 andγH2AX interaction for enhancing chemosensitivity in HCC ***,our study identifies ZCCHC4 as a new predictor of cancer poor prognosis and a potential target for improving chemotherapy effects,providing mechanistic insights to the roles of RBPs and their partners in cancer progression and chemoresistance.

关键词： damage resistance colon

Long noncoding RNAs in the metabolic control of inflammation and immune disorders

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Cellular & Molecular immunology 2019年第1期16卷 1-5页

作者： Junfang Xu Xuetao Cao Institute of immunology Zhejiang University School of MedicineHangzhou 310058China Department of immunology&center for immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

The metabolic control of immune cell development and function has been shown to be critical for the maintenance of immune homeostasis and is also involved in the pathogenesis of immune *** infections or cancers may induce metabolic reprogramming through different pathways to meet the energy and metabolite demands for pathogen propagation or cancer *** addition,some deregulated metabolites could trigger or regulate immune responses,thus causing chronic inflammation or immune disorders,such as viral infection,cancer and ***,the methods through which metabolism is regulated and the role of metabolic regulation in inflammation and immunity attract much *** regulation of inflammation and immunity is an emerging *** noncoding RNAs(lncRNAs)have been well documented to play crucial roles in many biological processes through diverse mechanisms,including immune regulation and metabolic ***,we review the functions and mechanisms of lncRNAs in the metabolic regulation of inflammatory immune disorders,aiming to deepen our understanding of the epigenetic regulation of inflammation and immunity.

关键词： inflammation immunity disorders

MicroRNA in vivo precipitation identifies miR-151-3p as a computational unpredictable miRNA to target Stat3 and inhibits innate IL-6 production

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Cellular & Molecular immunology 2018年第2期15卷 99-110页

作者： Xiang Liu Xiaoping Su Sheng Xu Huamin Wang Dan Han Jiangxue Li Mingyan Huang Xuetao Cao National Key Laboratory of Medical immunology&Institute of immunology Second Military Medical UniversityShanghai200433China Department of immunology&center for immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China Institute of immunology Zhejiang University School of MedicineHangzhou310058China

MicroRNAs(miRNAs)function as important regulators in the immune response and *** approaches have been reported to computationally predict miRNAs and their potential ***,there are still many miRNA–target interactions that are unpredictable by using the current computational *** established a miRNA in vivo precipitation method(miRIP)to identify unpredictable miRNAs with definite targets in these *** Stat3 is a well-known transcription factor involved in innate immunity and inflammation,we utilized the miRIP method to identify miRNAs that bind Stat3 mRNA in *** the captured miRNAs,miR-151-3p was confirmed to interact with Stat3 mRNA 3′-UTR and downregulate the Stat3 protein *** stimulation decreased miR-151-3p expression,thereby increasing IL-6 ***,we found that miR-151-3p inhibited LPS-induced IL-6 production by targeting *** data further confirmed miRIP as an efficient method to identify unpredictable miRNAs and explore miRNAs-mediated regulation in innate immunity and inflammation.

关键词： innate immunity IL-6 macrophage miR-151-3p Stat3

Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages

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Cellular & Molecular immunology 2020年第1期17卷 76-84页

作者： Xiang Chen Xingguang Liu Yunkai Zhang Wanwan Huai Qingqing Zhou Sheng Xu Xi Chen Nan Li Xuetao Cao National Key Laboratory of Medical immunology&Institute of immunology Second Military Medical UniversityShanghai 200433China Institute of immunology Zhejiang University School of MedicineHangzhou 310058China Department of immunology&center for immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

Epigenetic modification,including histone modification,precisely controls target gene *** posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated,whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further ***/tri-methylation modifications of histone 3 lysine 79(H3K79me2/3)have been shown to be associated with gene transcriptional *** of telomeric silencing-1-like(Dot1l)is the only known exclusive H3K79 methyltransferase and regulates the proliferation and differentiation of tumor ***,the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain ***,we found that H3K79me2/3 modification levels at the Il6 and Ifnb1 promoters,as well as H3K79me2 modification at the Tnfαpromoter,were increased in macrophages activated by Toll-like receptor(TLR)ligands or virus *** innate signals upregulated Dot1l expression in macrophages and THP1 ***1l silencing or a Dot1l inhibitor preferentially suppressed the production of IL-6 and interferon(IFN)-βbut not of TNFαin macrophages and THP1 cells triggered by TLR ligands or virus ***1l was recruited to the proximal promoter of the Il6 and Ifnb1 but not Tnfαgene and then mediated H3K79me2/3 modification at the Il6 and Ifnb1 promoters,consequently facilitating the transcription and expression of Il6 and ***,Dot1l-mediated selective H3K79me2/3 modifications at the Il6 and Ifnb1 promoters are required for the full activation of innate immune *** finding adds new insights into the epigenetic regulation of inflammatory responses and pathogenesis of autoimmune diseases.

关键词： H3K79me2/3 Dot1l epigenetic regulation IL-6 IFN-β macrophages inflammation