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

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 

机构地区：[1]CAS Key Laboratory of Pathogenic Microbiology and Immunology,Institute of Microbiology,Center for Biosafety Mega-Science,Chinese Academy of Sciences(CAS),Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100190,China [3]Ohio State University,Ohio,USA

出　　处：《Infectious Diseases & Immunity》2022年第3期183-192,共10页感染性疾病与免疫（英文）

基　　金：This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29040000);the Industrial innovation team grant from Foshan Industrial Technology Research Institute,Chinese Academy of Sciences,and the National Natural Science Foundation of China(32070163,81761128002,81871297).

摘　　要：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%(P<0.01).Endogenous gp96 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 

分 类 号：R512.62[医药卫生—内科学]