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HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication

Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma. However, the function and mechanism of the effect of HBV on host protein ubiquitination remain largely unknown. We aimed at characterizing whether and how HBV promotes self-replication by affecting host protein...

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Autores principales: Yuan, Sen, Xu, Jiaqi, Wang, Min, Huang, Junsong, Ma, Shuangshuang, Liu, Yang, Ke, Yujia, Zeng, Xianhuang, Wu, Kangwei, Wang, Jingwen, Tian, Xuezhang, Zheng, Dandan, Yousaf, Tanzeel, Naz, Wajeeha, Sun, Junwei, Chen, Lang, Guo, Deyin, Guo, Mingxiong, Sun, Guihong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676396/
https://www.ncbi.nlm.nih.gov/pubmed/36096451
http://dx.doi.org/10.1016/j.jcmgh.2022.09.003
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author Yuan, Sen
Xu, Jiaqi
Wang, Min
Huang, Junsong
Ma, Shuangshuang
Liu, Yang
Ke, Yujia
Zeng, Xianhuang
Wu, Kangwei
Wang, Jingwen
Tian, Xuezhang
Zheng, Dandan
Yousaf, Tanzeel
Naz, Wajeeha
Sun, Junwei
Chen, Lang
Guo, Deyin
Guo, Mingxiong
Sun, Guihong
author_facet Yuan, Sen
Xu, Jiaqi
Wang, Min
Huang, Junsong
Ma, Shuangshuang
Liu, Yang
Ke, Yujia
Zeng, Xianhuang
Wu, Kangwei
Wang, Jingwen
Tian, Xuezhang
Zheng, Dandan
Yousaf, Tanzeel
Naz, Wajeeha
Sun, Junwei
Chen, Lang
Guo, Deyin
Guo, Mingxiong
Sun, Guihong
author_sort Yuan, Sen
collection PubMed
description Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma. However, the function and mechanism of the effect of HBV on host protein ubiquitination remain largely unknown. We aimed at characterizing whether and how HBV promotes self-replication by affecting host protein ubiquitination. In this study, we identified UBXN7, a novel inhibitor for nuclear factor kappa B (NF-κB) signaling, was degraded via interaction with HBV X protein (HBx) to activate NF-κB signaling and autophagy, thereby affecting HBV replication. The expression of UBXN7 was analyzed by Western blot and quantitative reverse transcription polymerase chain reaction in HBV-transfected hepatoma cells and HBV-infected primary human hepatocytes (PHHs). The effects of UBXN7 on HBV replication were analyzed by using in vitro and in vivo assays, including stable isotope labeling by amino acids in cell culture (SILAC) analysis. Changes in HBV replication and the associated molecular mechanisms were analyzed in hepatoma cell lines. SILAC analyses showed that the ubiquitination of UBXN7 was significantly increased in HepG2.2.15 cells compared with control cells. After HBV infection, HBx protein interacted with UBXN7 to promote K48-linked ubiquitination of UBXN7 at K99, leading to UBXN7 degradation. On the other hand, UBXN7 interacted with the ULK domain of IκB kinase β through its ubiquitin-associating domain to facilitate its degradation. This in turn reduced NF-κB signaling, leading to reduced autophagy and consequently decreased HBV replication.
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spelling pubmed-96763962022-11-22 HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication Yuan, Sen Xu, Jiaqi Wang, Min Huang, Junsong Ma, Shuangshuang Liu, Yang Ke, Yujia Zeng, Xianhuang Wu, Kangwei Wang, Jingwen Tian, Xuezhang Zheng, Dandan Yousaf, Tanzeel Naz, Wajeeha Sun, Junwei Chen, Lang Guo, Deyin Guo, Mingxiong Sun, Guihong Cell Mol Gastroenterol Hepatol Original Research Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma. However, the function and mechanism of the effect of HBV on host protein ubiquitination remain largely unknown. We aimed at characterizing whether and how HBV promotes self-replication by affecting host protein ubiquitination. In this study, we identified UBXN7, a novel inhibitor for nuclear factor kappa B (NF-κB) signaling, was degraded via interaction with HBV X protein (HBx) to activate NF-κB signaling and autophagy, thereby affecting HBV replication. The expression of UBXN7 was analyzed by Western blot and quantitative reverse transcription polymerase chain reaction in HBV-transfected hepatoma cells and HBV-infected primary human hepatocytes (PHHs). The effects of UBXN7 on HBV replication were analyzed by using in vitro and in vivo assays, including stable isotope labeling by amino acids in cell culture (SILAC) analysis. Changes in HBV replication and the associated molecular mechanisms were analyzed in hepatoma cell lines. SILAC analyses showed that the ubiquitination of UBXN7 was significantly increased in HepG2.2.15 cells compared with control cells. After HBV infection, HBx protein interacted with UBXN7 to promote K48-linked ubiquitination of UBXN7 at K99, leading to UBXN7 degradation. On the other hand, UBXN7 interacted with the ULK domain of IκB kinase β through its ubiquitin-associating domain to facilitate its degradation. This in turn reduced NF-κB signaling, leading to reduced autophagy and consequently decreased HBV replication. Elsevier 2022-09-09 /pmc/articles/PMC9676396/ /pubmed/36096451 http://dx.doi.org/10.1016/j.jcmgh.2022.09.003 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Yuan, Sen
Xu, Jiaqi
Wang, Min
Huang, Junsong
Ma, Shuangshuang
Liu, Yang
Ke, Yujia
Zeng, Xianhuang
Wu, Kangwei
Wang, Jingwen
Tian, Xuezhang
Zheng, Dandan
Yousaf, Tanzeel
Naz, Wajeeha
Sun, Junwei
Chen, Lang
Guo, Deyin
Guo, Mingxiong
Sun, Guihong
HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication
title HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication
title_full HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication
title_fullStr HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication
title_full_unstemmed HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication
title_short HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication
title_sort hbv x protein induces degradation of ubxn7, a novel negative regulator of nf-κb signaling, to promote hbv replication
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9676396/
https://www.ncbi.nlm.nih.gov/pubmed/36096451
http://dx.doi.org/10.1016/j.jcmgh.2022.09.003
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