LncRNA NKILA inhibits HBV replication by repressing NF-κB signalling activation

Xi Zhang; Yuanyuan Li; Chen Huan; Yubao Hou; Rujia Liu; Hongyun Shi; Peng Zhang; Baisong Zheng; Yingchao Wang; Hong Wang; Wenyan Zhang

doi:10.1016/j.virs.2023.10.002

February 2024

. doi: 10.1016/j.virs.2023.10.002

Citation: Xi Zhang, Yuanyuan Li, Chen Huan, Yubao Hou, Rujia Liu, Hongyun Shi, Peng Zhang, Baisong Zheng, Yingchao Wang, Hong Wang, Wenyan Zhang. LncRNA NKILA inhibits HBV replication by repressing NF-κB signalling activation .VIROLOGICA SINICA, 2024, 39(1) : 44-55. http://dx.doi.org/10.1016/j.virs.2023.10.002

LncRNA NKILA通过调控NF-κB信号通路的激活抑制HBV病毒复制

张希 ^a,b,c ,
李园媛 ^b ,
桓晨 ^b ,
侯玉宝 ^b ,
刘如嘉 ^b ,
师鸿运 ^b ,
张鹏 ^a ,
郑柏松 ^b ,
王英超 ^d,, ,
王虹 ^a,b,, ,
张文艳 ^a,b,,

吉林大学, 吉林大学白求恩第一医院

通讯作者： 王英超, wangyingc@jlu.edu.cn; 王虹, wanghong_2020@jlu.edu.cn; 张文艳, zhangwenyan@jlu.edu.cn
收稿日期： 2023-08-09
录用日期： 2023-10-08

摘要

乙型肝炎病毒(HBV)感染会导致肝硬化和乙型肝炎病毒肝细胞性肝癌,HBx/NF-κB通路在HBV复制中的具有重要的调控作用。NF-κB相互作用的长非编码RNA (NKILA)作为NF-κB激活的抑制剂，调节乙型肝炎病毒的复制仍然很大程度上是未知的。在这项研究中，证实了NKILA通过抑制NF-κB活性来抑制HBV的复制。反过来，HBV感染下调NKILA的表达。此外，乙型肝炎病毒阳性患者的外周血来源单核细胞(PBMC)中，NKILA的表达水平低于健康人且与他们的乙型肝炎病毒载量均具有相关性。乙型肝炎病毒(HBV)阳性患者血清中NKILA表达水平与HBV病毒载量呈负相关。与HBV阴性细胞相比，表达1.3倍HBV基因组的HepG2细胞、HBV感染的HepG2-NTCP细胞和稳定产生HBV的HepG2.2.15和HepAD38细胞内源性NKILA水平也较低。此外，证实了HBx是NKILA介导的乙肝病毒复制抑制所必需的。NKILA通过阻断HBx和p65之间的相互作用来降低HBx诱导的NF-κB活化，而缺乏NF-B抑制的必需结构域的NKILA突变体失去了HBx诱导的NF-κB活化及抑制HBV复制的能力。总之，我们的数据表明NKILA通过调节NF-B信号通路抑制HBV复制。
- 长链非编码RNA
- , LncRNA NKILA
- , NF-κB信号通路,乙型肝炎病毒(HBV)
- , 病毒复制
- , HBx

LncRNA NKILA inhibits HBV replication by repressing NF-κB signalling activation

Xi Zhang ^a,b,c ,
Yuanyuan Li ^b ,
Chen Huan ^b ,
Yubao Hou ^b ,
Rujia Liu ^b ,
Hongyun Shi ^b ,
Peng Zhang ^a ,
Baisong Zheng ^b ,
Yingchao Wang ^d,, ,
Hong Wang ^a,b,, ,
Wenyan Zhang ^a,b,,

a. Department of Infectious Diseases, Center of Infectious Diseases and Pathogen Biology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130012, China;
b. Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, 130012, China;
c. Department of Ophthalmology, The First Hospital of Jilin University, Changchun, 130012, China;
d. Hepatobiliary Pancreatic Surgery, The First Hospital of Jilin University, Changchun, 130012, China

Corresponding author: Yingchao Wang, wangyingc@jlu.edu.cn Hong Wang, wanghong_2020@jlu.edu.cn Wenyan Zhang, zhangwenyan@jlu.edu.cn
Received Date: 09 August 2023
Accepted Date: 08 October 2023

Abstract

Hepatitis B virus (HBV) infection results in liver cirrhosis and hepatocellular carcinoma (HCC). HBx/nuclear factor (NF)-κB pathway plays a role in HBV replication. However, whether NF-κB-interacting long noncoding RNA (NKILA), a suppressor of NF-κB activation, regulates HBV replication remains largely unknown. In this study, gain-and-loss experiments showed that NKILA inhibited HBV replication by inhibiting NF-κB activity. In turn, HBV infection down-regulated NKILA expression. In addition, expression levels of NKILA were lower in the peripheral blood-derived monocytes (PBMCs) of HBV-positive patients than in healthy individuals, which were correlated with HBV viral loads. And a negative correlation between NKILA expression level and HBV viral loads was observed in blood serum from HBV-positive patients. Lower levels of endogenous NKILA were also observed in HepG2 cells expressing a 1.3-fold HBV genome, HBV-infected HepG2-NTCP cells, stable HBV-producing HepG2.2.15 and HepAD38 cells, compared to those HBV-negative cells. Furthermore, HBx was required for NKILA-mediated inhibition on HBV replication. NKILA decreased HBx-induced NF-κB activation by interrupting the interaction between HBx and p65, whereas NKILA mutants lack of essential domains for NF-κB inhibition, lost the ability to inhibit HBV replication. Together, our data demonstrate that NKILA may serve as a suppressor of HBV replication via NF-κB signalling.
- LncRNA
- , NF-κB-interacting long noncoding RNA (NKILA)
- , NF-κB signalling
- , Chronic hepatitis B virus (HBV)
- , Viral replication
- , HBx

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