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Histone deacetylase 4 inhibits NF-κB activation by facilitating IκBα sumoylation

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Journal of Molecular Cell Biology 2020年第12期12卷 933-945页

作者： Qi Yang jielin tang Chonghui Xu He Zhao Yuan Zhou Yanyi Wang Min Yang Xinwen Chen Jizheng Chen Department of Gastroenterology Guangzhou Women and Children's Medical CenterGuangzhou 510623China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China University of Chinese Academy of Sciences Beijing 100049China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China

Protein modification by small ubiquitin-like modifier(SUMO)is an important regulatory mechanism for multiple cellular *** the canonical pathway involving the ubiquitylation or phosphorylation of IκBα has been well characterized,little is known about the sumoylation of IkBa in the control of NF-κB ***,we find that histone deacetylase 4(HDAC4)negatively regulates tumor necrosis factor-alpha-or lipopolysaccharide-triggered NF-κB ***4 belongs to the SUMO E3 ligase family and can directly sumoylate IκBα.The cytoplasm location of HDAC4 is essential for IκBα*** Cys292 of HDAC4 is a key site for its SUMO E3 ligase *** sumoylation of IkBc prevents its polyubiquitination and degradation be-cause these two modifications occur both at the *** findings reveal a previously undiscovered role for HDAC4 in the inflammatory response as a SUMO E3 ligase for IκBα*** work provides insight into mechanisms ensuring optimal mediation of the NF-κB pathway.

关键词： histone deacetylase 4 sumoylation IκBα NF-κB SUMO E3 ligase

Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection

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Virologica Sinica 2023年第5期38卷 767-777页

作者： jielin tang Muqing Fu Chonghui Xu Bao Xue Anqi Zhou Sijie Chen He Zhao Yuan Zhou Jizheng Chen Qi Yang Xinwen Chen Guangzhou National Laboratory Guangzhou510005China State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou510530China GMU-GIBH Joint School of Life Sciences Guangzhou Medical UniversityGuangzhou511436China State Key Laboratory of Respiratory Disease Guangzhou Medical UniversityGuangzhou511436China

Tick-borne encephalitis virus(TBEV)is an important tick-borne pathogen that poses as a serious public health *** coverage and immunogenicity of the currently available vaccines against TBEV are relatively low;therefore,it is crucial to develop novel and effective vaccines against *** present study describes a novel strategy for the assembly of virus-like particles(VLPs)by co-expressing the structural(core/prM/E)and non-structural(NS2B/NS3Pro)proteins of *** efficacy of the VLPs was subsequently evaluated in C57BL/6 mice,and the resultant IgG serum could neutralize both Far-Eastern and European subtypes of *** findings indicated that the VLP-based vaccine elicited the production of cross-subtype reactive *** VLPs provided protection to mice lacking the type I interferon receptor(IFNAR^(-/-))against lethal TBEV challenge,with undetectable viral load in brain and intestinal ***,the group that received the VLP vaccine did not exhibit significant pathological changes and the inflammatory factors were significantly suppressed compared to the control *** with the VLP vaccine induced the production of multiple-cytokine-producing antiviral CD4+T cells in vivo,including TNF-α^(+),IL-2^(+),and IFN-γ^(+)T ***,the findings suggest that noninfectious VLPs can serve as a potentially safe and effective vaccine candidate against diverse subtypes of TBEV.

关键词： Tick-borne encephalitis virus(TBEV) Virus-like particle(VLP) Immunogenicity Neutralization Vaccine

Host HDAC4 regulates the antiviral response by inhibiting the phosphorylation of IRF3

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Journal of Molecular Cell Biology 2019年第2期11卷 158-169页

作者： Qi Yang jielin tang Rongjuan Pei XiaoXiao Gao Jing Guo Chonghui Xu Yun Wang QianWang Chunchen Wu Yuan Zhou Xue Hu He Zhao Yanyi Wang Xinwen Chen Jizheng Chen State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences Wuhan 430071 China University of Chinese Academy of Sciences Beijing 100049 China Key Laboratory of Human Functional Genomics of Jiangsu Province School of Basic Medical Science Nanjing Medical University Nanjing 210093 China

Class II HDACs, such as HDAC4, are critical regulators of the immune response in various immune cells;however, its role in innate immunity remains largely ***, we report that the overexpression of HDAC4 suppresses the production of type I interferons triggered by pattern-recognition receptors (PRRs). HDAC4 repressed the translocation of transcription factor IRF3 to the nucleus, thereby decreasing IRF3-mediated IFN-β expression. In particular, we also determined that HDAC4 can be phosphorylated and simultaneously block the phosphorylation of IRF3 at Ser386 and Ser396 by TBK1 and IKKε, respectively, by interacting with the kinase domain of TBK1 and IKKε. Furthermore, IFN-β may stimulate the expression of HDAC4. Our findings suggest that HDAC4 acts as a regulator of PRR signaling and is a novel mechanism of negative feedback regulation for preventing an overreactive innate immune response.

关键词： HDAC4 antiviral response IRF3 TBK1 IKKε

Comparison of viral propagation and drug response among SARS-CoV-2 VOCs using replicons capable of recapitulating virion assembly and release

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Virologica Sinica 2022年第5期37卷 695-703页

作者： Lingqian Tian Qiuhong Liu Rongjuan Pei Yingshan Chen Chonghui Xu jielin tang Hao Sun Kunpeng Liu Qi Yang Lei Yang Leshan Li Yongli Zhang Yuan Zhou Chao Shan Xue Hu Xinwen Chen Yun Wang State Key Laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan430071China University of Chinese Academy of Sciences Beijing100049China Department of Gastroenterology Guangzhou Women and Children's Medical CenterGuangzhou510623China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou510530China Innovation Center for Pathogen Research Guangzhou LaboratoryGuangzhou510320China

Several variants of concern(VOCs)have emerged since the WIV04 strain of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was first isolated in January *** to mutations in the spike(S)protein,these VOCs have evolved to enhance viral infectivity and immune ***,whether mutations of the other viral proteins lead to altered viral propagation and drug resistance remains *** replicon is a noninfectious viral surrogate capable of recapitulating certain steps of the viral life *** several SARS-CoV-2 replicons have been developed,none of them were derived from emerging VOCs and could only recapitulate viral genome replication and subgenomic RNA(sgRNA)*** this study,SARS-CoV-2 replicons derived from the WIV04 strain and two VOCs(the Beta and Delta variants)were prepared by removing the S gene from their genomes,while other structural genes remained *** replicons not only recapitulate viral genome replication and sgRNA transcription but also support the assembly and release of viral-like particles,as manifested by electron microscopic ***,the S-deletion replicon could recapitulate virtually all the post-entry steps of the viral life cycle and provides a versatile tool for measuring viral intracellular propagation and screening novel antiviral drugs,including inhibitors of virion assembly and *** the quantification of replicon RNA released into the supernatant,we demonstrate that viral intracellular propagation and drug response to remdesivir have not yet substantially changed during the evolution of SARS-CoV-2 from the WIV04 strain to the Beta and Delta VOCs.

关键词： SARS-CoV-2 Variants of concern(VOC) Viral-like particle(VLP) Replicon Remdesivir

Functions of human histone deacetylase 5(HDAC5) in the innate immune signaling pathways

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Functions of human histone deacetylase 5(HDAC5) in the innat...

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein

第十三届全国免疫学学术大会

作者： Chonghui Xu jielin tang Qi Yang Jizheng Chen Xinwen Chen State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences University of Chinese Academy of Sciences

As a member of the class IIa family of histone deacetylases, the histone deacetylase 5(HDAC5) is known to be a critical transcriptional regulator and linked to prominent human diseases, including cardiac diseases and *** we find that knockdown of HDAC5 in human cell lines and bone marrow-derived macrophages(BMDMs) from mice results in attenuated phosphorylation of p65 at ***, the levels of inflammation-related cytokines, such as TNF-α and IL-6, obviously reduced in cell culture supernatant after lipopolysaccharide(LPS) stimulation compared to the wild-type *** summary, our findings suggest that HDAC5 acts as a new regulator of anti-inflammatory responses.

关键词： histone deacetylase 5 innate immune anti-inflammatory response

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2970-2983页

作者： Qi Yang Bao Xue Fengjiang Liu Yongzhi Lu jielin tang Mengrong Yan Qiong Wu Ruyi Chen Anqi Zhou Lijie Liu Junjun Liu Changbin Qu Qingxin Wu Muqing Fu Jiayi Zhong Jianwei Dong Sijie Chen Fan Wang Yuan Zhou Jie Zheng Wei Peng Jinsai Shang Xinwen Chen Guangzhou National Laboratory Guangzhou 510005China State Key Laboratory of Respiratory Disease Guangzhou Medical UniversityGuangzhou 511436China Wuhan Institute of Virology Chinese Academy of SciencesWuhan 430071China School of Basic Medical Sciences Guangzhou Medical UniversityGuangzhou 511436China GMUGIBH Joint School of Life Sciences Guangzhou Medical UniversityGuangzhou 511436China Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203China School of Pharmaceutical Science and Technology Hangzhou lnstitute for Advanced StudyUCASHangzhou 310024China

Respiratory syncytial virus(RSV)is the major cause of bronchiolitis and pneumonia in young children and the *** are currently no approved RSV-specific therapeutic small molecules *** high-throughput antiviral screening,we identified an oral drug,the prenylation inhibitor lonafarnib,which showed potent inhibition of the RSV fusion *** exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells(HBEC).Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry,but has farnesyltransferase-independent antiviral ***-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion *** at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody ***,lonafarnib dose-dependently reduced the replication of RSV in BALB/c ***,lonafarnib could be a potential fusion inhibitor for RSV infection.

关键词： neutral metastable approved

Desulfuromonas alkenivorans S-7联合稻壳处理酸性重金属废水

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煤炭学报 2019年第9期44卷 2851-2858页

作者：佘臣杰唐婕琳何环张朦童丽唐俊陶秀祥中国矿业大学化工学院江苏徐州221116 中国矿业大学煤炭加工与高效洁净利用教育部重点实验室江苏徐州221116 中国矿业大学安全工程学院江苏徐州221116

为了研究硫酸盐还原菌和稻壳联合生物反应器在重金属废水处理中作用及机理。利用实验室前期分离鉴定的硫酸盐还原菌 Desulfuromonas alkenivorans S-7联合填充稻壳柱式生物反应器处理人工合成酸性重金属(Fe 3+,Mn 2+,Cr 6+)废水。比较... 详细信息

为了研究硫酸盐还原菌和稻壳联合生物反应器在重金属废水处理中作用及机理。利用实验室前期分离鉴定的硫酸盐还原菌 Desulfuromonas alkenivorans S-7联合填充稻壳柱式生物反应器处理人工合成酸性重金属(Fe 3+,Mn 2+,Cr 6+)废水。比较了废水处理过程中理化特性(pH, E h , E c )及3种重金属离子变化规律,并利用FT-IR光谱仪分析了微生物和稻壳联合处理作用下重金属离子去除特性。研究结果表明:S-7能够明显提高酸性废水的pH,20 d后pH 最终稳定在6.20左右,也能使反应体系维持在较高的还原环境并降低体系的电导率。S-7菌株对3种代表性离子都有一定的处理效果,对Fe,Mn,Cr三种金属离子的去除效率分别为Fe>Mn>Cr。反应器处理前期废水中离子的去除速率较快,后期由于离子共存对废水处理的影响使废水中金属离子浓度趋于平衡,出现动态制约平衡,S-7菌株对3种重金属离子的去除机制可能存在差异。处理后期由于Cr 6+浓度上升明显,增大了SRB反应器中的重金属含量,明显影响SRB反应器的稳定性能;稻壳填充对S-7菌株生长能够稳定维持SRB反应器的厌氧环境,并且稻壳对金属离子去除也存在一定程度的物理吸附作用。FT-IR分析表明:S-7菌体处理废水时会吸附Fe,Mn,Cr离子,其中羟基、胺基、酰胺基及羧基是发生吸附作用重要的官能团;稻壳在处理重金属废水前后,稻壳的Si—O—Si和羰基在处理重金属废水中可能发挥了作用。

关键词：硫酸盐还原菌生物反应器重金属离子傅里叶红外光谱(FT-IR)

Functional characterization of the human histone deacetylase 3(HDAC3) in the innate immune signaling pathways

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Functional characterization of the human histone deacetylase...

Intranasal adenovirus-vectored Omicron vaccine induced nasal immunoglobulin A has superior neutralizing potency than serum antibodies

第十三届全国免疫学学术大会

作者： jielin tang Qi Yang Chonghui Xu He Zhao Dongwei Gai Jizheng Chen Xinwen Chen State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences University of Chinese Academy of Sciences

The histone deacetylase 3(HDAC3) has high expression in terminally differentiated tissue;however, its role in innate immunity remains largely unknown. Here, we report that HDAC3 act as a positive regulator, depending on its’ deacetyl ability, regulated the activation of type I interferon mediated by double-stranded RNA or DNA by targeting TBK1. HDAC3-deficient mice reduced the production of type I interferon and were more susceptibility to lethal viral infection compared to wild-type. HDAC3 directly regulated Lys K241 and K692 deacetylation of TBK1, while deacetylation of these sites was critical for the kinase activity of TBK1. Therefore, our work provided molecular insights into the mechanisms by which HDAC3 directly maintained the deacetylation status of TBK1 and enhanced its kinase activity.

关键词： HDAC3 Innate immune response TBK1 deacetylation

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3507-3518页

作者： Si Chen Zhengyuan Zhang Qian Wang Qi Yang Li Yin Lishan Ning Zhilong Chen jielin tang Weiqi Deng Ping He Hengchun Li Linjing Shi yjun Deng Zijian Liu Hemeng Bu Yaohui Zhu Wenming Liu Linbing Qu Ligiang Feng Xiaoli Xiong Baoqing Sun Nanshan Zhong Feng Li ingchao Li Xinwen Chen Ling Chen Guangzhou Institute of Infectious Disease Guangzhou Eighth People's HospitalGuangzhou Medical UniversityGuangzhouChina Guangzhou National Laboratory GuangzhouChina State Key Laboratory of Respiratory Disease Center for Cell Lineage ResearchGuangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina University of Chinese Academy of Sciences BeijingChina State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Xiamen United Institute of Respiratory Health XiamenChina

The upper respiratory tract is the initial site of SARS-CoV-2 *** spike-specific secretory immunoglobulin A(slgA)correlates with protection against Omicron breakthrough *** report that intranasal vaccination using human adenovirus serotype 5(Ad5)vectored Omicron spike in people who previously vaccinated with ancestral vaccine could induce robust neutralizing slgA in the nasal *** slgA was predominantly present in dimeric and multimeric forms and accounted for nearly 40%of total proteins in nasal mucosal lining fluids(NMLFs).A low-level IgG could also be detected in NMLFs but not IgM,IgD,and *** a complete nasal wash,slgA in the nasal passage could be replenished rapidly within a few hours.A comparison of purified paired serum IgA,serum IgG,and nasal slgA from the same individuals showed that slgA was up to 3-logs more potent than serum antibodies in binding to spikes and in neutralizing Omicron *** IgG and IgA failed to neutralize XBB and BA.2.86,while nasal slgA retained potent neutralization against these newly emerged *** analysis showed that slgA Was more effective than IgG or IgA in blocking spike-mediated cell-to-cell transmission and protecting hACE2 mice from XBB *** a slgA monoclonal antibody as a reference,we estimated that the total nasal slgA contains about 2.6-3.9%spikespecific slgA in NMLFs collected approximately one month after intranasal *** study provided insights for developing intranasal vaccines that can induce slgA to build an effective and mutation-resistant first-line immune barrier against constantly emerging variants.

关键词： nasal antibodies neutral