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SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3- TBK1 complex

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Protein & Cell 2014年第5期5卷 369-381页

作者： Xiaojuan Chen xingxing Yang Yang Zheng Yudong Yang yaling xing Zhongbin Chen Division of Infection and Immunity Department of Electromagnetic and Laser Biology Beijing Institute of Radiation Medicine_ Beijing 100850 China Anhui Medical University Hefei 230032 China

SARS coronavirus （SARS-CoV） develops an antagonis- tic mechanism by which to evade the antiviral activities of interferon （IFN）. Previous studies suggested that SARS-CoV papain-like protease （PLpro） inhibits activa- tion of the IRF3 pathway, which would normally elicit a robust IFN response, but the mechanism（s） used by SARS PLpro to inhibit activation of the IRF3 pathway is not fully known. In this study, we uncovered a novel mechanism that may explain how SARS PLpro effi- ciently inhibits activation of the IRF3 pathway. We found that expression of the membrane-anchored PLpro domain （PLpro-TM） from SARS-CoV inhibits STING/ TBKl/IKKE-mediated activation of type I IFNs and dis- rupts the phosphorylation and dimerization of IRF3, which are activated by STING and TBKI. Meanwhile, we showed that PLpro-TM physically interacts with TRAF3, TBK1, IKK~, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex for activa- tion of IFN expression. However, the interaction between the components in STING-TRAF3-TBK1 complex is dis- rupted by PLpro-TM. Furthermore, SARS PLpro-TM reduces the levels of ubiquitinated forms of RIG-I, STING, TRAF3, TBK1, and IRF3 in the STING-TRAF3- TBK1 complex. These results collectively point to a new mechanism used by SARS-CoV through which PLpro negatively regulates IRF3 activation by interaction withSTING-TRAF3-TBK1 complex, yielding a SARS-CoV countermeasure against host innate immunity.

关键词： SARS coronavirus papain-like protease,interferon deubiquitinase STING-TRAF3-TBK1 complex

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Coronavirus membrane-associated papain-like proteases induce autophagy through interacting with Beclinl to negatively regulate antiviral innate immunity

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Protein & Cell 2014年第12期5卷 912-927页

作者： Xiaojuan Chen Kai Wang yaling xing Jian Tu xingxing Yang Qian Zhao Kui Li Zhongbin Chen Division of Infection and Immunity Department of Electromagnetic and Laser Biology Beijing Institute of Radiation Medicine Beijing 100850 China Department of Immunology Bengbu Medical College Bengbu 233030 China Prince of Wales Clinical School The University of New South Wales Sydney NSW 2052 Australia Department of Microbiology Immunology and Biochemistry University of Tennessee Health Science Center Memphis TN 38163 USA

Autophagy plays important roles in modulating viral replication and antiviral immune response. Coronavirus infection is associated with the autophagic process, however, little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses. Here, we show that the membrane-associated papain-like protease PLP2 （PLP2-TM） of coronaviruses acts as a novel autophagy- inducing protein. Intriguingly, PLP2-TM induces incom- plete autophagy process by increasing the accumula- tion of autophagosomes but blocking the fusion of autophagosomes with lysosomes. Furthermore, PLP2- TM interacts with the key autophagy regulators, LC3 and Beclinl, and promotes Beclinl interaction with STING, the key regulator for antiviral IFN signaling. Finally, knockdown of Beclinl partially reverses PLP2-TM＇s inhibitory effect on innate immunity which resulting in decreased coronavirus replication. These results sug- gested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclinl, which in turn modulates coronavirus replication and antiviral innate immunity.

关键词： coronavirus papain-like proteaseautophagy antiviral immunity Beclinl STING

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新型冠状病毒PLpro负调控DDX3诱导的β干扰素抗病毒免疫通路

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军事医学 2024年第6期48卷 453-460页

作者：王明宇陈晓娟孟欢邵丽婷焦园园李文倩李萍邢雅玲军事科学院军事医学研究院生物信息中心军事科学院军事医学研究院辐射医学研究所首都医科大学附属地坛医院检验科

目的发现严重急性呼吸综合征冠状病毒2(SARS-CoV-2)木瓜样蛋白酶（PLpro）的宿主互作分子，探索其生物学意义。方法邻近蛋白标记结合质谱分析筛选宿主互作分子DEAD-box解旋酶3(DDX3)；免疫荧光法分析PLpro与DDX3的胞内共定位；免疫共... 详细信息

目的发现严重急性呼吸综合征冠状病毒2(SARS-CoV-2)木瓜样蛋白酶（PLpro）的宿主互作分子，探索其生物学意义。方法邻近蛋白标记结合质谱分析筛选宿主互作分子DEAD-box解旋酶3(DDX3)；免疫荧光法分析PLpro与DDX3的胞内共定位；免疫共沉淀法分析PLpro与DDX3的相互作用，以及PLpro对DDX3与IκB激酶ε(IKKε)和TANK结合激酶1(TBK1)、DDX3与线粒体抗病毒信号蛋白（MAVS）互作的影响；荧光素酶报告基因法检测PLpro对β干扰素（IFN-β）通路的影响和对底物的酶切效率。结果 DDX3能够与PLpro发生细胞内共定位和相互作用；PLpro可能抑制DDX3-MAVS复合体形成，抑制DDX3-IKKε-TBK1之间的相互作用，负调控Ⅰ型干扰素通路；DDX3过表达情况下，PLpro/PLP-TM对底物位点的切割效率显著升高，而DDX3表达降低时，切割效率则显著降低。结论 DDX3可能是PLpro的宿主相互作用分子之一；PLpro负调控DDX3活化的IFN-β表达，为病毒复制提供有利的免疫环境，提升蛋白酶切割活性，共同促进病毒复制。

关键词：严重急性呼吸综合征冠状病毒2 木瓜样蛋白酶 DEAD-box解旋酶3 抗病毒天然免疫

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Proteolytic Processing,Interferon antagonist and Deubiquitinase Activies of the Papain-like Protease of the New Emerging Middle East Respiratory Syndrome Coronavirus

Proteolytic Processing,Interferon antagonist and Deubiquitin...

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第八届全国医学生物化学与分子生物学第五届全国临床应用生...

作者： xingxing Yang Xiaojuan Chen yaling xing Zhongbin Chen Division of Infection and Immunity Beijing Institute of Radiation Medicine Beijing Institute of Radiation Medicine Anhui Medical University

The newly emergent Middle East respiratory syndrome coronavirus(MERS-CoV)causes severe pulmonary disease in human beings,represents the second example of a highly pathogenic coronavirus followed by the first of SARS-CoV.Genomic studies revealed that only two viral proteases,papain-like protease(PLpro)and 3C-like protease(3CLpro),which process the polyproteins encoded by the MERS-CoV genomic RNA.We previously showed that SARS-CoV

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Coronavirus papain-like proteases induce autophagy but block autophagosome fusion with lysosomes through interacting with Beclinl

Coronavirus papain-like proteases induce autophagy but block...

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细胞—生命的基础——中国细胞生物学学会2013年全国学...

作者： Zhongbin Chen Kai Wang Xiaojuan Chen yaling xing xingxing Yang Beijing Institute of Radiation Medicine

关键词： Coronavirus NL63 Papain-like protease Autophagy Beclinl STING

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Coronavirus papain-like proteases induce autophagy but block autophagosome fusion with lysosomes through interacting with Beclin 1

Coronavirus papain-like proteases induce autophagy but block...

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第八届全国医学生物化学与分子生物学第五届全国临床应用生...

作者：陈忠斌 Kai Wang Xiaojuan Chen yaling xing xingxing Yang 军事医学科学院放射与辐射医学研究所 Beijing Institute of Radiation Medicine

Autophagy is a cellular catabolic process that sequesters cargo in double-membraned autophagosome and delivers the cargo to lysosomes to be degraded for recycling resource for cells.Autophagy plays important roles in modulating viral replication and antiviral innate and adaptive immune response.Previous studies demonstrated that coronavirus infection is associated with the autophagic process,however,the underlying mechanisms for autophagy induction are largely unknown.Here,we show that the papain-like proteases(PLP) of human coronavirus(HCoV) NL63 induce autophagy.We found that the transmembrane(TM) form of the papain-like protease PLP2(PLP2-TM) acts as a novel autophagy-inducing protein encoded by coronavirus.Intriguingly,PLP2-TM induces incomplete autophagy process,as PLP2-TM increases the accumulation of autophagosomes but blocks the fusion of autophagosomes with lysosomes,leading to prevention of the degradation of the autophagic substrate,p62.Furthermore,PLP2-TM colocalizes and interacts with autophagy marker protein LC3.Interestingly,PLP2-TM interacts and deubiquitinates Beclinl to upregulate Beclinl expression and promote Beclinl interaction with STING,the key regulator for antiviral IFN signaling.Together,these results suggested that the coronavirus papain-like proteases induce incomplete autophagy by interacting with Beclin 1,which in turn may modulate coronavirus replication and antiviral innate immunity.

关键词： Coronavirus NL63 Papain-like protease Autophagy Beclinl STING

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5'-triphosphate-siRNA against survivin gene induces interferon production and inhibits proliferation of lung cancer cells in vitro

5'-triphosphate-siRNA against survivin gene induces interfer...

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第九届全国免疫学学术大会

作者： yaling xing Xiaojuan Chen Kai Wang Fei Yan xingxing Yang Zhongbin Chen Beijing Institute of Radiation Medicine

Survivin is a new member of the inhibitors of apoptosis(IAPs)family and upregulated in various human malignancies including human lung cancer.In this study,we proposed a new strategy for RNA interference(RNAi)-mediated anticancer therapy that combining activation of IFN production with RNAi using 5’-triphosphate-siRNA(3p-siRNA)against survivin gene.We designed and generated 3p-siRNA targeting human survivin gene(3p-survivin-siRNA).The findings reported here demonstrated that 3p-survivin-siRNA induced a 3p-dependent type-I IFN response when transfected into human lung cancer cells.The 3p-survivin-siRNA significantly inhibited lung cancer cell proliferation in a 3p-dependent manner.The anticancer effect of 3p-survivin-siRNA was superior to that of conventional siRNA.The expression level of survivin in 3p-survivin-siRNA-treated A549 cells was significantly lower than that of siRNA.Furthermore,when 3p-survivin-siRNA silencing approach was combined with radiation treatment,3p-survivin-siRNA increases the cytotoxicity of A549 cells and induces more cells underwent apoptosis.In conclusion,our results suggest that 3p-survivin-siRNA could act as a powerful bifunctional molecule with potential for developing promising radiosensitization therapeutics against human lung cancer.

关键词： 5’-triphosphated siRNA IFNa/b lung cancer cell RNAi survivin

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Coronavirus papain-like proteases induce incomplete autophagy through interacting with Beclin 1 to negatively regulate antiviral innate immunity

Coronavirus papain-like proteases induce incomplete autophag...

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第九届全国免疫学学术大会

作者： Zhongbin Chen Xiaojuan Chen Kai Wang yaling xing xingxing Yang Qian Zhao Beijing Institute of Radiation Medicine

Autophagy plays important roles in modulating viral replication and antiviral immune response.Coronavirus infection is associated with the autophagic process,however,little is known about the mechanisms of autophagy induction and its contribution to coronavirus regulation of host innate responses.Here,we show that the membrane-associated papain-like protease PLP2(PLP2-TM)of coronaviruses acts as a novel autophagy-inducing protein.Intriguingly,PLP2-TM induces incomplete autophagy process by increasing the accumulation of autophagosomes but blocking the fusion of autophagosomes with lysosomes.Furthermore,PLP2-TM interacts with the key autophagy regulators,LC3 and Beclinl,and promotes Beclinl interaction with STING,the key regulator for antiviral IFN signaling.Finally,Knockdown of Beclin 1partially reverses PLP2-TM’s inhibitory effect on innate immunity which resulting in decreased coronavirus replication.These results suggested that coronavirus papain-like protease induces incomplete autophagy by interacting with Beclin 1,which in turn modulates coronavirus replication and antiviral innate immunity.

关键词： Coronavirus Papain-like protease Autophagy Antiviral immunity Beclinl STING

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LRRC23激活RIG-Ⅰ信号通路对流感病毒复制的影响

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中国生物制品学杂志 2023年第9期36卷 1062-1071页

作者：朱艳慧杨芳芳王鑫邢雅玲刘雅琳河南中医药大学河南郑州450046 天津中医药大学天津301617 军事科学院军事医学研究院辐射医学研究所北京100850

目的探讨LRRC23(leucine rich repeat containing 23)激活RIG-Ⅰ信号通路对流感病毒复制的影响。方法通过在A549细胞中过表达和敲低LRRC23,探讨其对流感病毒复制的影响。将pcLRRC23质粒和siLRRC23(small interfering LRRC23)分别转染A549细胞,24 h后感染A/京防/1/86(H1N1),空斑试验和ELISA法分别检测细胞上清中流感病毒滴度和HA蛋白表达水平;qRT-PCR和Western blot法分别检测LRRC23、RIG-Ⅰ、MAVS、流感病毒M1基因及HA蛋白的表达水平;免疫荧光和免疫共沉淀试验(co-immunoprecipitation,Co-IP)检测LRRC23与RIG-Ⅰ的相互作用;双荧光素酶报告基因分析试验检测IFN-β-luc和NF-κB-luc活性。结果过表达LRRC23可显著降低流感病毒A549细胞上清中流感病毒滴度,抑制HA蛋白的表达。过表达LRRC23通过激活RIG-Ⅰ-MAVS信号通路,增强流感病毒刺激的IFN-β和NF-κB激活,抑制流感病毒M1基因和HA蛋白的表达。相反,敲低LRRC23可增加流感病毒感染A549细胞上清中HA蛋白的表达;上调流感病毒M1基因相对表达量,下调RIG-ⅠmRNA和MAVS mRNA相对表达量。结论LRRC23通过激活RIG-Ⅰ信号通路抑制流感病毒复制,在抗病毒天然免疫中发挥重要作用。

关键词：流感病毒 LRRC23 RIG-Ⅰ信号通路 HA蛋白

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全基因转录组测序分析双氢青蒿素改善脂多糖诱导小鼠急性肺损伤机制

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中国药理学与毒理学杂志 2023年第12期37卷 914-922页

作者：杨鲁霞张孝昌李擎宇魏振桥黄曼琼焦园园邢雅玲王升启河南中医药大学药学院河南郑州450046 军事科学院军事医学研究院生物信息中心北京100850

目的基于全基因转录组测序技术分析双氢青蒿素(DHA)改善脂多糖(LPS)诱导小鼠急性肺损伤(ALI)的作用及机制。方法ip给予LPS 10 mg·kg-1诱导ALI小鼠模型。模型成功后,ip给予DHA 20 mg·kg-1(模型+DHA组),同时设正常对照组,每组10只。给药... 详细信息

目的基于全基因转录组测序技术分析双氢青蒿素(DHA)改善脂多糖(LPS)诱导小鼠急性肺损伤(ALI)的作用及机制。方法ip给予LPS 10 mg·kg-1诱导ALI小鼠模型。模型成功后,ip给予DHA 20 mg·kg-1(模型+DHA组),同时设正常对照组,每组10只。给药24 h后,取肺测定小鼠肺湿/干重比(W/D);制备并计数肺泡灌洗液(BALF)中炎症细胞数;苏木精-伊红染色法观察小鼠肺组织病理改变;酶联免疫吸附法(ELISA)检测BALF中白细胞介素1β(IL-1β),IL-6和肿瘤坏死因子α(TNF-α)分泌水平,实时荧光定量PCR(RT-qPCR)检测肺组织中IL-1β,IL-6和TNF-αmRNA表达水平。全基因转录组测序,结合生物信息分析筛选小鼠肺组织差异表达基因,进行GO和KEGG通路富集分析,并进行RT-qPCR验证。结果与模型组相比,模型+DHA组小鼠肺W/D值显著降低(P<0.01),病理损伤显著减轻,BALF中各类炎症细胞显著降低(P<0.01);肺组织中IL-1β,IL-6和TNF-αmRNA表达均显著降低(P<0.05)。全基因转录组测序及生物信息分析发现,ALI模型小鼠肺组织内免疫相关的胎盘特异蛋白8(Plac8)、Toll样受体7基因(TLR7)显著上调(P<0.01),给予DHA干预后则均显著下调(P<0.05,P<0.01)。RT-qPCR验证结果显示,模型+DHA组ALI小鼠肺组织中Plac8和TLR7基因表达变化趋势与转录组测序结果一致。GO和KEGG通路富集分析显示,Plac8和TLR7基因的作用主要与细胞因子生成调控、T/B细胞活化及其信号转导、趋化因子信号转导、NF-κB信号转导等相关,即与机体对外界应激而产生的炎症反应和免疫应答相关。结论DHA可减轻LPS诱导的ALI小鼠肺水肿,改善肺部炎症,减轻ALI,其作用机制可能与其降低TLR7和Plac8 mRNA表达、负调控其参与的信号转导通路,进而调控炎症相关细胞因子分泌和免疫细胞活化等免疫反应有关。

关键词：双氢青蒿素急性肺损伤免疫调节炎症转录组测序胎盘特异蛋白8 Toll样受体7

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