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MHC Class I Assembly Function and Intracellular Transport Routes for Hepatitis B Virus Antigen Cross-presentation by Heat Shock Protein gp96

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Infectious Diseases & Immunity 2022年第3期2卷 183-192页

作者： Lijuan Qin Yongai Liu Yuxiu Xu Yang Li Jun Hu Ying Ju Yu Zhang Shuo Wang Zihai Li Changfei Li Xin Li Songdong Meng CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyCenter for Biosafety Mega-ScienceChinese Academy of Sciences(CAS)Beijing 100101China University of Chinese Academy of Sciences Beijing 100190China Ohio State University OhioUSA

Background:During hepatitis B virus(HBV)infection,virus-infected hepatocytes directly cross-present viral antigens and regulate T cell response within the liver microenvironment.However,little is known regarding the regulatory pathways involved in viral antigen presentation in HBV-infected hepatocytes.This study investigated the underlying mechanism of antigen assembly and the HBV antigen-presenting function of major histocompatibility complex(MHC)class I molecules using heat shock protein gp96.Methods:First,western blotting,flow cytometry,co-immuno precipitation,GST pull-down,and confocal microscopic assays were performed to determine whether endogenous gp96 affects MHC-I levels via an antigen presentation pathway.Second,the B3Z assay and an AAV/HBV-infected hepatocyte-specific gp96-deficient mouse model were used to determine whether gp96 knockout functionally impaired peptide cross-presentation and produced a weakened antiviral cytotoxic T cell(CTL)response both in vivo and in vitro.Finally,confocal microscopic analysis and the B3Z assay were employed to show that exogenous gp96-associated peptide was present in MHC-I molecules via the endoplasmic reticulum(ER)-Golgi secretory pathway.Results:Compared with the control,gp96 knockdown significantly reduced the cell surface levels of MHC-I by approximately 75%(Pgp96 interacts with MHC-I and is involved in antigen presentation.Moreover,a weakened antiviral CTL response(34%compared to control mice)has been observed in hepatocyte-specific gp96-deficient mice following HBV infection.gp96 directed exogenous antigen to the ER,and the exogenous gp96-chaperoned peptide was endosome-and proteasome-dependent but not transporter associated with antigen processing dependent.Conclusions:Cellular gp96 promotes the assembly and antigen presentation of MHC class I molecules.In addition,extracellular gp96 served as a natural adjuvant to induce a CTL response in a concerted and regulated manner within different cellular compartments.Our results elucidate the mech

关键词： Hepatitis B virus Antigen cross-presentation Cytotoxic T-cell gp96

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Cellular gp96 upregulates AFP expression by blocking NR5A2 SUMOylation and ubiquitination in hepatocellular carcinoma

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Journal of Molecular Cell Biology 2023年第5期15卷 66-79页

作者： Liyuan Qian Zhentao Liang Zihao Wang Jiuru Wang Xin Li Jingmin Zhao Zihai Li Lizhao Chen Yongai Liu Ying Ju Changfei Li Songdong Meng Key Laboratory of Pathogen Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeĳing 100101China University of Chinese Academy of Science Beĳing 100049China Department of Pathology and Hepatology The Fifth Medical CentreChinese PLA General HospitalBeĳing 100039China Pelotonia Institute for Immuno-Oncology The Ohio State University Comprehensive Cancer Center—The JamesColumbusOH 43210USA

Alpha-fetoprotein (AFP) is the most widely used biomarker for the diagnosis of hepatocellular carcinoma (HCC). However, asubstantial proportion of HCC patients have either normal or marginally increased AFP levels in serum, and the underlyingmechanisms are not fully understood. In the present study, we provided in vitro and in vivo evidence that heat shock protein gp96promoted AFP expression at the transcriptional level in HCC. NR5A2 was identified as a key transcription factor for the AFP gene, andits stability was enhanced by gp96. A further mechanistic study by co-immunoprecipitation, GST pull-down, and molecular dockingshowed gp96 and the SUMO E3 ligase RanBP2 competitively binding to NR5A2 at the sites spanning from aa 507 to aa 539. Thebinding of gp96 inhibited SUMOylation, ubiquitination, and subsequent degradation of NR5A2. In addition, clinical analysis of HCCpatients indicated that gp96 expression in tumors was positively correlated with serum AFP levels. Therefore, our study uncovered anovel mechanism that gp96 regulates the stability of its client proteins by directly affecting their SUMOylation and ubiquitination.These findings will help in designing more accurate AFP-based HCC diagnosis and progression monitoring approaches.

关键词： gp96 AFP NR5A2 RanBP2 SUMOylation

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Immunogenicity of multi-epitope-based vaccine candidates administered with the adjuvant gp96 against rabies

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Virologica Sinica 2016年第2期31卷 168-175页

作者： Yange Niu Ye Liu Limin Yang Hongren Qu Jingyi Zhao Rongliang Hu Jing Li Wenjun Liu Key Laboratory of Pathogenic Microbiology and Immunology Institute of Microbiology ChineseAcademy of Sciences Beijing 100101 China University of Chinese Academy of Sciences Beijing 100049 China Laboratory of Epidemiology and Key Laboratory of Jilin Province for Zoonosis Prevention and Control Veterinary Research Institute Academy of Military Medical Sciences Changchun 130122 China Beijing Center for Animal Disease Control and Prevention Chinese Veterinary Medical Association of Animal Clinic Branch Beijing 102629 China State Key Laboratory of Veterinary Biotechnology Harbin Veterinary Research Institute Chinese Academy of Agricultural Sciences Harbin 150001 China

Rabies, a zoonotic disease, causes > 55,000 human deaths globally and results in at least 500 million dollars in losses every year. The currently available rabies vaccines are mainly inactivated and attenuated vaccines, which have been linked with clinical diseases in animals. Thus, a rabies vaccine with high safety and efficacy is urgently needed. Peptide vaccines are known for their low cost, simple production procedures and high safety. Therefore, in this study, we examined the efficacy of multi-epitope-based vaccine candidates against rabies virus. The ability of various peptides to induce epitope-specific responses was examined, and the two peptides that possessed the highest antigenicity and conservation, i.e., AR16 and h PAB, were coated with adjuvant caninegp96 and used to prepare vaccines. The peptides were prepared as an emulsion of oil in water(O/W) to create three batches of bivalent vaccine products. The vaccine candidates possessed high safety. Virus neutralizing antibodies were detected on the day 14 after the first immunization in mice and beagles, reaching 5–6 IU/m L in mice and 7–9 IU/m L in beagles by day 28. The protective efficacy of the vaccine candidates was about 70%–80% in mice challenged by a virulent strain of rabies virus. Thus, a novel multi-epitope-based rabies vaccine with gp96 as an adjuvant was developed and validated in mice and dogs. Our results suggest that synthetic peptides hold promise for the development of novel vaccines against rabies.

关键词：狂犬病疫苗 gp96 免疫原性多表位疫苗注射佐剂狂犬病病毒候选疫苗

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A strategy to produce monoclonal antibodies against gp96 by prime-boost regimen using endogenous protein and E.coli heterologously-expressed fragment

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Journal of Central South University 2011年第6期18卷 1857-1864页

作者：张誉丹操胜孟颂东高福 CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences Graduate University Chinese Academy of Sciences Research Network of Immunity and Health (rNIH) Beijing Institutes of Life Science

gp96, a member of HSP90 family, is a versatile molecular chaperone with various newly-discovered functions, for example to serve as a low affinity, high capacity calcium binding protein, a natural adjuvant for therapeutic cancer vaccines, a tumor rejection antigen, an immune regulator to pathological cell death. Its multi-functional and structural characteristics make it also an interesting target to develop antibody-based therapeutics. However, its low immunogenicity to mice, because of its high-sequence similarity among different species, is an obstacle to obtain valuable monoclonal antibodies (MAbs). This is a common problem for any low immunogenic proteins, whose sequences share close identity between mice and other species. Here, a new strategy of priming was employed by swine endogenous full-length gp96 and then boosting by E. coli-system heterologously expressed gp96 N-terminal fragment (N-355) to generate MAbs. Twelve different highly-specific MAbs against swine/human endogenous gp96 were successfully obtained. The binding activities of these MAbs were confirmed by enzyme-linked immunosorbent assay (ELISA), Western blot (WB), immunofluorescence and flow cytometry analysis. This provides some important reagents for further research and potential therapeutics. The methods employed can be used for MAb production of any sequence-highly-conserved proteins between mice and swine/human (or any other species).

关键词：单克隆抗体钙结合蛋白大肠杆菌表达 gp96 内源性异源酶联免疫吸附试验流式细胞仪分析

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Immunotherapy with heat shock protein 96 to treat gliomas

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中华神经外科杂志(英文) 2021年第1期6卷 53-57页

作者： Li Chunzhao Du Yifei Zhang Yang Ji Nan Beijing 100038 Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University No.119 South 4th Ring West Road Fengtai District Beijing 100070 China Beijing Shijitan Hospital No.10 Yangfangdian Road

Heat shock protein 96 (gp96) is a highly conserved protein in the endoplasmic reticulum. The functions of gp96 include promoting the oncogenesis and progression of glioma. In addition, tumor-derived gp96 can activate anti-tumor immune. Therefore, this protein was used to generate an anti-tumor vaccine and widely applied to glioma therapy. This review summarizes the mechanisms of gp96 in glioma oncogenesis and clinical trials of the gp96 tumor vaccine in glioma treatment.

关键词： Glioma gp96 Tumor vaccine Oncogenesis

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HEAT SHOCK PROTEIN gp96 AND CANCER IMMUNOTHERAPY

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Chinese Medical Sciences Journal 2002年第4期17卷 251-256页

作者：岳培彬杨树德黄常志 Cancer Institute & Hospital CAMS & PUMC Beijing 100021 National Center for Clinical Laboratory Beijing Hospital Ministry of Health Beijing 100730

Heat shock protein gp96 is a highly conserved and monomorphic glycoprotein in the endoplasmic reticulum.It functions as molecular chaperone and can associate with a variety of antigenic peptides noncovalently in vivo and in vitro. Recent studies have indicated that gp96 molecules participate in major histocompatibility complex class I - restricted antigen presentation pathway. Immunization of mice with gp96 preparations isolated from cancer cells can elicit a cancer - specific protective T cell immune response that is recallable, which is a prerequisite for gp96 as a therapeutic vaccine against cancers. The immunogenicity of gp96 molecules has been attributed to the antigenic peptides associated with them. These phenomena provide a new pathway for cancer immunotherapy. The mechanism that the gp96 -peptide complex induces specific immune response and the explorations for gp96 - peptide complex as a therapeutic cancer vaccine are reviewed.

关键词：热休克蛋白 gp96 癌症免疫疗法 HSPs 疫苗

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Prophylactic cancer vaccine, from concept to reality?

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Chinese Science Bulletin 2014年第10期59卷 944-949页

作者： Bao Zhao Xin Li Beinan Wang Bin Gao Songdong Meng Key Laboratory of Pathogenic Microbiology and Immunology Institute of Microbiology Chinese Academy of Sciences

The demonstration that for infectious diseases vaccine-induced immunity is in principle only effective before rather than after infection occurs,provides valuable insights in understanding the nature of immune system and the challenges in cancer treatment.Besides the already known underlying counter-back mechanisms,the astronomical numbers of tumor cells in established tumors could overwhelm the limited amount of specific T cells induced by vaccination,which may account for the modest efficiency of immunotherapy against cancer.We speculate that the long window period for cancer development will allow immune-intervening strategies(e.g.,the proper prophylactic vaccination)to promote adaptive mechanisms toward an enhanced immunosurveillance,which could effectively eradicate or at least control the few precancerous cells undergoing neoplastic transformation during early premalignant stages in cancer development,and protect the host from lethal tumor formation.It should be emphasized that the pre-cancer-associated antigens but not the tumorassociated antigens seem to be the suitable antigens for designing prophylactic cancer vaccines.In addition,an ideal prophylactic cancer vaccine may contain multiple pre-cancer-associated antigens,which will provide broad and effective immune protection in a heterogeneous human population.Finally,we demonstrated that placenta-derived gp96,which can be readily obtained in high amount for vaccination,has the ability to initiate antitumor T-cell immunity via association with multiple embryo-cancer antigens.Further understanding placental gp96 associated with carcinoembryonic antigen repertoires that orchestrate immune defense networks against cancer formation will allow to provide an effective prophylactic approach in cancer prevention.

关键词： Prophylactic cancer vaccine gp96 Placenta Carcinoembryonic antigens Multivalentvaccine

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gp96蛋白的免疫学及其临床应用研究进展

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生物工程学报 2011年第5期27卷 704-711页

作者：陈才伟贾晓娟孟颂东刘文军中国科学院微生物研究所中国科学院病原微生物与免疫学重点实验室北京100101

热休克蛋白gp96属于HSP90家族,是内质网中最丰富的蛋白质之一,在细胞内发挥着分子伴侣的作用。在天然免疫中,gp96则通过与Toll样受体等相互作用刺激抗原呈递细胞(如DC等)产生各种细胞因子激活免疫系统;而在获得性免疫中,gp96-抗原肽复... 详细信息

热休克蛋白gp96属于HSP90家族,是内质网中最丰富的蛋白质之一,在细胞内发挥着分子伴侣的作用。在天然免疫中,gp96则通过与Toll样受体等相互作用刺激抗原呈递细胞(如DC等)产生各种细胞因子激活免疫系统;而在获得性免疫中,gp96-抗原肽复合物通过抗原交叉将抗原肽呈递给MHC-Ⅰ类分子,诱发机体抗原特异性细胞毒T细胞免疫应答,清除病原物感染和肿瘤;近年来的研究还发现gp96具有免疫佐剂的功能。以下从gp96的生物学特性、免疫学机制以及其在抗病原感染和抗肿瘤免疫中的应用等方面做一小结,为设计以gp96-抗原肽为新一代疫苗的临床研究提供理论基础。

关键词：热休克蛋白 gp96 免疫佐剂抗原交叉呈递

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热休克蛋白HSP70和gp96增强乙肝DNA疫苗的细胞和体液免疫应答

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生物工程学报 2011年第5期27卷 790-798页

作者：王彦中王赛锋张小俊李杨赵世宇孟颂东中国科学院微生物研究所中国科学院病原微生物与免疫学重点实验室北京100101 中国科学院研究生院北京100049 北京天坛生物制品股份有限公司北京100024

旨在以乙肝病毒（HBV）的主要结构蛋白-表面蛋白（HBsAg）和核心蛋白（HBcAg）作为抗原设计DNA疫苗,研究热休克蛋白HSP70和gp96作为新型免疫佐剂增强疫苗的细胞免疫和体液免疫水平。利用酶联免疫斑点实验、流式细胞内因子染色、3H-TdR... 详细信息

旨在以乙肝病毒（HBV）的主要结构蛋白-表面蛋白（HBsAg）和核心蛋白（HBcAg）作为抗原设计DNA疫苗,研究热休克蛋白HSP70和gp96作为新型免疫佐剂增强疫苗的细胞免疫和体液免疫水平。利用酶联免疫斑点实验、流式细胞内因子染色、3H-TdR实验、酶联免疫吸附实验技术分析,结果显示HSP70和gp96可使疫苗的细胞免疫水平提高1~6倍,提高体液免疫水平20%~60%。研究结果为设计以HSP70和gp96作为免疫佐剂的新型乙肝治疗性疫苗提供了依据。

关键词：乙肝治疗性疫苗 HSP70 gp96 佐剂

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热激蛋白gp96免疫学功能及在主动免疫治疗肿瘤和传染病中的应用

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生物工程学报 2012年第3期28卷 261-266页

作者：徐亚星王赛锋张小俊孟颂东中国科学院微生物研究所中国科学院病原微生物与免疫学重点实验室北京100101

热激蛋白gp96可特异性结合来源于肿瘤和病毒的抗原肽,与抗原呈递细胞表面CD91等受体作用进入胞内,并在内质网中将结合的抗原通过抗原呈递链呈递给MHCI类分子,激活特异性T细胞。同时,与细胞表面Toll样受体(TLR)TLR2、TLR4等相互作用,激... 详细信息

热激蛋白gp96可特异性结合来源于肿瘤和病毒的抗原肽,与抗原呈递细胞表面CD91等受体作用进入胞内,并在内质网中将结合的抗原通过抗原呈递链呈递给MHCI类分子,激活特异性T细胞。同时,与细胞表面Toll样受体(TLR)TLR2、TLR4等相互作用,激活天然免疫。近期研究发现调节性T细胞(Treg)对gp96免疫功能有显著抑制作用,随着对影响gp96免疫功能的免疫抑制机制的深入了解,以及利用汉逊酵母表达有免疫活性的全长gp96蛋白体系的建立,gp96将在治疗肿瘤及传染性疾病中发挥更大的作用。

关键词： gp96 T细胞调节性T细胞肿瘤传染病

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