{"doi":"10.1016/j.jcmgh.2022.09.003","title":"HBV X Protein Induces Degradation of UBXN7, a Novel Negative Regulator of NF-κB Signaling, to Promote HBV Replication","abstract":"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. 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. SummaryOur results reveal that HBx can promote HBV replication via degradation of UBXN7, thus maintaining high levels of IKK-β to activate NF-κB signaling and NF-κB–dependent autophagy. Our findings suggest that UBXN7 can be targeted for potential new therapies in HBV-related diseases. Our results reveal that HBx can promote HBV replication via degradation of UBXN7, thus maintaining high levels of IKK-β to activate NF-κB signaling and NF-κB–dependent autophagy. Our findings suggest that UBXN7 can be targeted for potential new therapies in HBV-related diseases. Chronic hepatitis B virus (HBV) infection is a major global health problem worldwide. Two hundred fifty-seven million people chronically infected by HBV are at increased risk of death from hepatocellular carcinogenesis.1Organization W.H. Global hepatitis report, 2017. Global Hepatitis Report. 2017; : 2017Google Scho","journal":"Cellular and Molecular Gastroenterology and Hepatology","year":2022,"id":273143,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":940170,"name":"Jiaqi Xu","orcid":"0000-0002-4883-7358","position":1,"is_corresponding":false},{"id":940171,"name":"Min Wang","orcid":"0000-0001-8816-3952","position":2,"is_corresponding":false},{"id":940637,"name":"Junsong Huang","orcid":null,"position":3,"is_corresponding":false},{"id":940172,"name":"Shuangshuang Ma","orcid":"0000-0001-7206-1804","position":4,"is_corresponding":false},{"id":940173,"name":"Yang Liu","orcid":"0000-0001-8095-2009","position":5,"is_corresponding":false},{"id":940638,"name":"Yujia Ke","orcid":null,"position":6,"is_corresponding":false},{"id":893454,"name":"Xianhuang Zeng","orcid":null,"position":7,"is_corresponding":false},{"id":940639,"name":"Kang-Wei Wu","orcid":null,"position":8,"is_corresponding":false},{"id":940174,"name":"Jingwen Wang","orcid":"0000-0002-3450-9046","position":9,"is_corresponding":false},{"id":940640,"name":"Xuezhang Tian","orcid":null,"position":10,"is_corresponding":false},{"id":396776,"name":"Dandan Zheng","orcid":"0000-0001-8934-267X","position":11,"is_corresponding":false},{"id":940641,"name":"Tanzeel Yousaf","orcid":null,"position":12,"is_corresponding":false},{"id":940642,"name":"Wajeeha Naz","orcid":null,"position":13,"is_corresponding":false},{"id":892823,"name":"Junwei Sun","orcid":"0000-0003-2532-0361","position":14,"is_corresponding":false},{"id":700265,"name":"Lang Chen","orcid":"0000-0002-6000-6653","position":15,"is_corresponding":false},{"id":860590,"name":"Deyin Guo","orcid":"0000-0002-8297-0814","position":16,"is_corresponding":false},{"id":892828,"name":"Mingxiong Guo","orcid":"0000-0001-7680-0272","position":17,"is_corresponding":false},{"id":892829,"name":"Guihong Sun","orcid":"0000-0003-4451-7135","position":18,"is_corresponding":false},{"id":893457,"name":"Sen Yuan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T00:27:52.048702Z","pmid":"36096451","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}