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PI4P STimulatING innate immune activation:beyond the Golgi

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Cellular & Molecular Immunology 2023年第12期20卷 1399-1400页

作者： Yi Zheng Xuejing Zhang chengjiang gao Key Laboratory of Infection and Immunity of Shandong Province Department of ImmunologySchool of Basic Medical SciencesShandong UniversityJinan250012ShandongChina

The cGAS–STING pathway is pivotal for sensing cytosolic DNA[2].cGAS,a cytoplasmic DNA sensor,can be stimulated by DNA,and it consumes ATP and GTP to synthesize a second messenger,2'3'-cGAMP,which binds to STING,resulting in STING conformational change,oligomerization,and activation;ultimately,this process leads to the production of cytokines such as type I interferon to mediate antiviral and antitumor immune responses(Fig.1).Phosphoinositides,derived from phosphatidylinositol(PI),are phospholipids in membranes and are also crucial signaling molecules[3].The D-3,D-4,or D-5 positions in the inositol head group can be phosphorylated;therefore,a total of seven different PIP molecules exist in eukaryotes.Phosphatidylinositol 4-phosphate(PI4P)is distributed in various membrane components,with the highest amount in the trans-Golgi network(TGN)[4].The PI4P level in cells is regulated by its PI4K synthetases(PI4KA,PI4KB,PI4K2A,and PI4K2B)and the lipid phosphatase SAC1.In addition to being a precursor for PIP2 and PIP3,PI4P is a crucial signaling molecule involved in vesicular transport,lipid transport,and organelle morphology maintenance.

关键词： activation positions synthesize

USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation

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Cellular & Molecular Immunology 2022年第10期19卷 1141-1152页

作者： Wanxin Zhuang Lei Zhang Yi Zheng Bingyu Liu Chunhong Ma Wei Zhao Suxia Liu Feng Liu chengjiang gao Key Laboratory of Infection and Immunity of Shandong Province&Key Laboratory for Experimental Teratology of Ministry of Education Shandong UniversityJinanShandong250012PR China Department of Immunology School of Biomedical SciencesShandong UniversityJinanShandong250012PR China

Inflammasomes are essential components of the innate immune system and its defense against infections,whereas the dysregulation of inflammasome activation has a detrimental effect on human health.The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis,yet the underlying mechanism remains elusive.Here,we identify USP3 as a direct deubiquitinating enzyme(DUB)for ASC,the central adapter mediating the assembly and activation of most inflammasomes.USP3 removes the K48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation.Additionally,USP3 promotes inflammasome activation,and this function was confirmed in mouse models of aluminum(Alum)-induced peritonitis,F.novicida infection and flagellin-induced pneumonia in vivo.Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation,and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.

关键词： ASC inflammasome K48-linked ubiquitination proteasomal degradation USP3

MAVS-loaded unanchored Lys63-linked polyubiquitin chains activate the RIG-I-MAVS signaling cascade

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Cellular & Molecular Immunology 2023年第10期20卷 1186-1202页

作者： Feng Liu Wanxin Zhuang Bin Song Yuan Yang Junqi Liu Yi Zheng Bingyu Liu Jie Zheng Wei Zhao chengjiang gao Key Laboratory of Infection and Immunity of Shandong Province&Key Laboratory for Experimental Teratology of Ministry of Education Shandong UniversityJinan250012ShandongP.R.China Department of Immunology School of Biomedical SciencesShandong UniversityJinan250012ShandongP.R.China Shanghai Institute of Materia Medica Chinese Academy of Sciences201203ShanghaiP.R.China Department of Pathogenic Biology School of Biomedical SciencesShandong UniversityJinan250012ShandongP.R.China

The adaptor molecule MAVS forms prion-like aggregates to govern the RIG-I-like receptor(RLR)signaling cascade.Lys63(K63)-linked polyubiquitination is critical for MAVS aggregation,yet the underlying mechanism and the corresponding E3 ligases and deubiquitinating enzymes(DUBs)remain elusive.Here,we found that the K63-linked polyubiquitin chains loaded on MAVS can be directly recognized by RIG-I to initiate RIG-I-mediated MAVS aggregation with the prerequisite of the CARDRIG-I-CARDMAVS interaction.Interestingly,many K63-linked polyubiquitin chains attach to MAVS via an unanchored linkage.We identified Ube2N as a major ubiquitin-conjugating enzyme for MAVS and revealed that Ube2N cooperates with the E3 ligase Riplet and TRIM31 to promote the unanchored K63-linked polyubiquitination of MAVS.In addition,we identified USP10 as a direct DUB that removes unanchored K63-linked polyubiquitin chains from MAVS.Consistently,USP10 attenuates RIG-I-mediated MAVS aggregation and the production of type I interferon.Mice with a deficiency in USP10 show more potent resistance to RNA virus infection.Our work proposes a previously unknown mechanism for the activation of the RLR signaling cascade triggered by MAVS-attached unanchored K63-linked polyubiquitin chains and establishes the DUB USP10 and the E2:E3 pair Ube2N-Riplet/TRIM31 as a specific regulatory system for the unanchored K63-linked ubiquitination and aggregation of MAVS upon viral infection.

关键词： MAVS Aggregation Unanchored K63-linked polyubiquitin chains RIG-l USP10

SARS-CoV-2 NSP5 and N protein counteract the RIG-I signaling pathway by suppressing the formation of stress granules

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Signal Transduction and Targeted Therapy 2022年第2期7卷 531-542页

作者： Yi Zheng Jian Deng Lulu Han Meng-Wei Zhuang Yanwen Xu Jing Zhang Mei-Ling Nan Yang Xiao Peng Zhan Xinyong Liu chengjiang gao Pei-Hui Wang Key Laboratory of Infection and Immunity of Shandong Province Department of ImmunologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute Cheeloo College of MedicineShandong UniversityJinan 250012China Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong University44 West Culture Road250012 JinanShandongPR China China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province 44 West Culture Road250012 JinanShandongPR China Suzhou Research Institute Shandong UniversityShandong UniversitySuzhouJiangsu 215123China

As a highly pathogenic human coronavirus,SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread.The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity.However,whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive.In this study,SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule(avSG)formation.Moreover,NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA,poly(I:C),inhibiting TBK1 and IRF3 phosphorylation,and restraining the nuclear translocalization of IRF3.Furthermore,HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection.Mechanistically,NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity.In contrast to the multiple targets of NSP5,the N protein specifically targeted cofactors upstream of RIG-I.The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I.Additionally,the N protein also affected the recognition of dsRNA by RIG-I.This study revealed the intimate correlation between SARS-CoV-2,the stress response,and innate antiviral immunity,shedding light on the pathogenic mechanism of COVID-19.

关键词： NSP5 immunity stress

不同基质对云南沙棘嫩枝扦插生根过程及苗木品质的影响

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东北林业大学学报 2024年第6期52卷 12-19,26页

作者：杨红高文于吕庆鑫阮成江丁健西藏农牧学院林芝860000 大连民族大学

为探究不同基质对云南沙棘嫩枝扦插生根过程及苗木品质的影响,采用随机区组试验,选择细河沙(T1)、腐殖土(T2)、珍珠岩(T3)、珍珠岩+腐殖土(T4)、细河沙+珍珠岩(T5)及细河沙+腐殖土(T6)等6种基质,综合评价不同基质条件下云南沙棘扦插苗... 详细信息

为探究不同基质对云南沙棘嫩枝扦插生根过程及苗木品质的影响,采用随机区组试验,选择细河沙(T1)、腐殖土(T2)、珍珠岩(T3)、珍珠岩+腐殖土(T4)、细河沙+珍珠岩(T5)及细河沙+腐殖土(T6)等6种基质,综合评价不同基质条件下云南沙棘扦插苗生根过程及苗木品质,筛选适宜云南沙棘嫩枝扦插的基质。结果表明:(1)T1基质密度最大、总孔隙度最小,与其他各基质间差异达极显著水平(P<0.01),T3基质田间持水量最小,其次是T4,二者与其他各基质间差异极显著(P<0.01);基质pH以T3最小,显著低于其他各基质(P<0.05),有机质、全氮、全磷、全钾、碱解氮、速效磷、速效钾、阳离子交换量均以T2基质最大,且与其他各基质间差异极显著(P<0.01);(2)不同基质沙棘插穗生根率由大到小表现为:T1、T5、T6、T3、T4、T2,相关性分析表明,在扦插初期,物理指标对插穗生根的影响大于化学指标;(3)从生理指标来看,总叶绿素质量分数由大到小均表现为:T2、T4、T6、T1、T5、T3,根系活力以T1最强,与其他各基质间差异显著(P<0.05),T1基质的插穗和根系丙二醛(MDA)质量摩尔浓度、脱落酸(ABA)质量分数均显著低于其他各基质(P<0.05),赤霉素(GAs)质量分数、脯氨酸(Pro)、吲哚乙酸(IAA)质量分数高于其他各基质,插穗及根系过氧化物酶(POD)和超氧化物歧化酶(SOD)活力均T1最大,w(IAA)∶w(ABA)值均以T1最大,T2最小。细河沙基质各化学指标含量均低于其他各基质,但插穗生根率及其他生理指标基本优于其他各基质,可见沙棘嫩枝插穗在不定根形成过程中无需基质提供过多养分。建议在沙棘嫩枝扦插时优先选择具有廉价、易得、环保等特征的细河沙作为扦插基质,但在生根后需要及时补充营养物质以保证其正常生长。

关键词：基质扦插云南沙棘生根率理化指标生理指标

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) membrane (M) protein inhibits type I and IIIinterferon production by targeting RIG-I/MDA-5 signaling

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Signal Transduction and Targeted Therapy 2021年第1期6卷 171-183页

作者： Yi Zheng Meng-Wei Zhuang Lulu Han Jing Zhang Mei-Ling Nan Peng Zhan Dongwei Kang Xinyong Liu chengjiang gao Pei-Hui Wang Key Laboratory of Infection and Immunity of Shandong Province Department of ImmunologySchool of Basic Medical SciencesCheeloo College of MedicineShandong University250012 JinanChina Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute Cheeloo College of MedicineShandong University250012 JinanChina Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong University44 West Culture Road250012 JinanShandongPR China China–Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province 44 West Culture Road250012 JinanShandongPR China Suzhou Research Institute Shandong UniversityShandong UniversitySuzhouJiangsu 215123China

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has quickly spread worldwide and has affected more than 10 million individuals.A typical feature of COVID-19 is the suppression of type I and III interferon(IFN)-mediated antiviral immunity.However,the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive.Here,we reported that the SARS-CoV-2 membrane(M)protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling.In addition,the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly(I:C)transfection.Mechanistically,the SARS-CoV-2 M protein interacts with RIG-I,MAVS,and TBK1,thus preventing the formation of the multiprotein complex containing RIG-I,MAVS,TRAF3,and TBK1 and subsequently impeding the phosphorylation,nuclear translocation,and activation of IRF3.Consequently,ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus.Taken together,these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling,which subsequently attenuates antiviral immunity and enhances viral replication.This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.

关键词： immunity acute MAVS

Hepatitis B virus evades immune recognition via RNA adenosine deaminase ADAR1-mediated viral RNA editing in hepatocytes

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Cellular & Molecular Immunology 2021年第8期18卷 1871-1882页

作者： Liyuan Wang Yang Sun Xiaojia Song Zehua Wang Yankun Zhang Ying Zhao Xueqi Peng Xiaodong Zhang Chunyang Li chengjiang gao Nailin Li Lifen gao Xiaohong Liang Zhuanchang Wu Chunhong Ma Key Laboratory for Experimental Teratology Ministry of EducationSchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandongChina Department of Immunology School of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandongChina Key Laboratory of Infection and Immunity of Shandong Province Shandong UniversityJinanChina Advanced Medical Research Institute Shandong UniversityJinanChina Clinical Pharmacology Group Department of MedicineSolnaKarolinska InstituteStockholmSweden

HBV is considered as a“stealth”virus that does not invoke interferon(IFN)responses;however,the mechanisms by which HBV bypasses innate immune recognition are poorly understood.In this study,we identified adenosine deaminases acting on RNA 1(ADAR1),which is a key factor in HBV evasion from IFN responses in hepatocytes.Mechanically,ADAR1 interacted with HBV RNAs and deaminated adenosine(A)to generate inosine(I),which disrupted host immune recognition and thus promoted HBV replication.Loss of ADAR1 or its deficient deaminase activity promoted IFN responses and inhibited HBV replication in hepatocytes,and blocking the IFN signaling pathways released the inhibition of HBV replication caused by ADAR1 deficiency.Notably,the HBV X protein(HBx)transcriptionally promoted ADAR1 expression to increase the threshold required to trigger intrinsic immune activation,which in turn enhanced HBV escape from immune recognition,leading to persistent infection.Supplementation with 8-azaadenosine,an ADAR1 inhibitor,efficiently enhanced liver immune activation to promote HBV clearance in vivo and in vitro.Taken together,our results delineate a molecular mechanism by which HBx promotes ADAR1-derived HBV immune escape and suggest a targeted therapeutic intervention for HBV infection.

关键词： ADAR1 RNA editing IFN response HBV replication HBx

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8^+ T Cells in a Mouse Model of Hepatitis B Virus Infection

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Cellular & Molecular Immunology 2009年第1期6卷 35-43页

作者： Ying Ju Nan Hou Xiaoning Zhang Di Zhao Ying Liu Jinjin Wang Fang Luan Wei Shi Faliang Zhu Wensheng Sun Lining Zhang chengjiang gao Lifen gao Xiaohong Liang Chunhong Ma Institute of Immunology Shandong University School of Medicine 44 Wenhua Xi Road Jinan Shandong 250012 China The Key Laboratory of Cardiovascular Remodeling and Function Research Chinese Ministry of Education and Chinese Ministry of Health Shandong University Qilu Hospital 107 Wenhua Xi Road Jinan Shandong 250012 China Key Laboratory for Experimental Teratology of the Ministry of Education China

T cell immunoglobulin- and mucin-domain-containing molecule-3 （Tim-3） has been reported to participate in the pathogenesis of inflammatory diseases. However, whether Tim-3 is involved in hepatitis B virus （HBV） infection remains unknown. Here, we studied the expression and function of Tim-3 in a hydrodynamics-based mouse model of HBV infection. A significant increase of Tim-3 expression on hepatic T lymphocytes, especially on CD8^＋ T cells, was demonstrated in HBV model mice from day 7 to day 18. After Tim-3 knockdown by specific shRNAs, significantly increased IFN-γ production from hepatic CD8^＋ T cells in HBV model mice was observed. Very interestingly, we found Tim-3 expression on CD8^＋ T cells was higher in HBV model mice with higher serum anti-HBs production. Moreover, Tim-3 knockdown influenced anti-HBs production in vivo. Collectively, our data suggested that Tim-3 might act as a potent regulator of antiviral T-cell responses in HBV infection. Cellular ＆ Molecular Immunology.

关键词： Tim-3 HBV CD8^＋ T cell hydrodynamic injection shRNA

TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity

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Signal Transduction and Targeted Therapy 2021年第9期6卷 2794-2808页

作者： Xueer Wang Honghai Zhang Zhugui Shao Wanxin Zhuang Chao Sui Feng Liu Xiaorong Chen Jinxiu Hou Lingli Kong Hansen Liu Yi Zheng Bingyu Liu Tian Chen Lei Zhang Xinming Jia chengjiang gao Shandong Provincial Key Laboratory of Infection and Immunity&Department of Immunology School of Biomedical SciencesShandong UniversityJinanShandongChina Department of Pathogenic Biology School of Biomedical SciencesShandong UniversityJinanShandongChina Clinical Medicine Scientific and Technical Innovation Center Shanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina

Spleen tyrosine kinase(SYK)is a non-receptor tyrosine kinase,which plays an essential role in both innate and adaptive immunity.However,the key molecular mechanisms that regulate SYK activity are poorly understood.Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation.We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK.This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors(CLRs).

关键词： SYK immunity ubiquitin