IR@PKUHSC  > 北京大学第九临床医学院
学科主题临床医学
HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function
Liu, Ningning1; Zhang, Jinfang1; Yang, Xiaohai2; Jiao, Tong1,3; Zhao, Xin4; Li, Wenxia5; Zhu, Jianhua6; Yang, Pu6; Jin, Jianping7; Peng, Jirun5,8,9; Li, Zhiwei4; Ye, Xin1,3,10
通讯作者Li, Zhiwei(4) ; Ye, Xin(1,3,10)
刊名JOURNAL OF VIROLOGY
2017-08-01
DOI10.1128/JVI.00340-17
91期:16
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Virology
研究领域[WOS]Virology
关键词[WOS]HEPATOCELLULAR-CARCINOMA ; NEDD8 CONJUGATION ; HEPATOMA-CELLS ; PROTEIN ; P53 ; DEGRADATION ; MDM2 ; UBIQUITINATION ; TRANSCRIPTION ; ANTAGONIZES
英文摘要

Hepatitis B virus (HBV)-encoded X protein (HBx) plays a critical role in HBV-related hepatocarcinoma development. In this study, we demonstrate that HBx is specifically modified by NEDD8. We found that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability by preventing its ubiquitination-mediated degradation. Consistently, analysis of 160 hepatocellular carcinoma patient specimens indicated that the amount of HDM2 protein correlates with HBx protein level. We identified that HBx K91 and K95 as the key HBx NEDDylation sites and observed that the NEDDylation-deficient HBx has shorter half-life. We generated Huh7 cell lines which ectopically express wild-type and NEDDylation-deficient HBx and found that NEDDylation-deficient HBx showed less chromatin localization and less DDB1 binding. Consistently, the expression of HBx-regulated genes (IL-8, MMP9, and YAP) and HBV transcription (the activity of HBV enhancer and the amount of pgRNA transcribed from cccDNA) were significantly higher in cells expressing wild-type (WT) HBx than that in cells expressing mutant HBx. In addition, HBx-expressing cells proliferated faster than control and mutant HBx-expressing cells. We also showed that the ability of WT HBx-expressing cells to form tumors in nude mice was significantly higher than that of mutant HBx-expressing cells. In conclusion, we revealed that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability and chromatin localization, which in turn favors HBx-dependent transcriptional regulation, cell proliferation, and HBV-driven tumor growth.

IMPORTANCE Hepatitis B virus (HBV) HBx protein plays a critical role in viral replication and hepatocarcinogenesis. However, the regulation of HBx stability is not well understood. We found that HBx is modified by NEDD8 and that the HDM2 E3 ligase promotes HBx NEDDylation to enhance HBx stability by inhibiting its ubiquitination. We provide a new evidence to show the positive correlation between HDM2 and HBx in clinical hepatocellular carcinoma (HCC) samples. We also identified the major NEDDylation sites on HBx. Our studies indicate that the defective NEDDylation of HBx negatively affects its ability to activate the transcription of downstream genes and promote cell proliferation and tumor growth in vivo. Taken together, our findings reveal a novel posttranslational modification of HBx by HDM2 which regulates its stability, subcellular localization, and functions. These findings indicate that HDM2 is an important regulator on HBx and a potential diagnosis/ therapeutic marker for HBV-associated HCC.

语种英语
WOS记录号WOS:000406406600007
通讯作者邮箱lzw302@126.com ; yex@im.ac.cn
ISSN0022-538X
引用统计
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/139843
专题北京大学第九临床医学院
作者单位1.Chinese Acad Sci, Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Beijing, Peoples R China;
2.Anhui Univ, Inst Hlth Sci, Hefei, Anhui, Peoples R China;
3.Univ Chinese Acad Sci, Beijing, Peoples R China;
4.PLA, Hosp 302, Beijing, Peoples R China;
5.Capital Med Univ, Dept Surg, Shijitan Hosp, Beijing, Peoples R China;
6.Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA;
7.Peking Univ, Sch Clin Med 9, Beijing, Peoples R China;
8.Capital Med Univ, Sch Oncol, Beijing, Peoples R China;
9.Peoples Liberat Army Gen Hosp, Affiliated Hosp 1, Beijing, Peoples R China;
10.Univ Chinese Acad Sci, Savaid Med Sch, Beijing, Peoples R China
推荐引用方式
GB/T 7714
Liu, Ningning,Zhang, Jinfang,Yang, Xiaohai,et al. HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function[J]. JOURNAL OF VIROLOGY,2017,91(16).
APA Liu, Ningning.,Zhang, Jinfang.,Yang, Xiaohai.,Jiao, Tong.,Zhao, Xin.,...&Ye, Xin.(2017).HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function.JOURNAL OF VIROLOGY,91(16).
MLA Liu, Ningning,et al."HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function".JOURNAL OF VIROLOGY 91.16(2017).
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