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Hepatitis B virus infection is an important global health problem and one of the main causes of hepatitis.
At present, the number of chronic hepatitis B virus infections in the world is 350 to 400 million, and 75% of the infected people are Asians.
Liver diseases and liver cancer associated with HBV infection are extremely common in China, causing about 400,000 liver cancer deaths every year.
Unlike the new coronavirus, cases of vertical infection in childhood are the main way for HBV to infect humans.
About 25% of patients infected with hepatitis B virus will develop liver fibrosis or liver cancer in adulthood.
Generally speaking, most adults (about 65%) have basically no obvious symptoms after being infected with HBV.
Finally, the body will clear HBV from the body, suggesting that HBV infection in adults is self-limiting, and its mechanism is unknown.
On April 5th, researcher Hu Ronggui from the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences, Professor Deng Qiang from Fudan University School of Basic Medicine, Professor Zhang Jiming from Huashan Hospital of Fudan University, and Professor Xu Ping from the National Phoenix Center for Protein Science were the co-corresponding authors.
The Journal of Hepatology published a research paper titled: Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection.
The study found that the P gene and X gene of hepatitis B virus (Hepatitis B virus, HBV) each encode a homologous isoform HpZ/P' and HBxZ, which can inhibit HBV replication.
The study also discovered a translation regulatory element located in the HBV enhancer I region.
The research uses transcriptome sequencing technology (RNA-sequencing) combined with ribosome profiling technology (ribosome profiling), combined with quantitative proteomics to systematically analyze the interaction between HBV and the host.
By studying a recently developed 1.
0-fold HBV recombinant cccDNA system, the researchers discovered a translation regulatory element EnhI-SL (stem loop within enhancer I) located in the enhancer I region of the HBV genome.
Cell studies have shown that mutations destroy its stem loop The structure can enhance the expression of reporter gene or HBV polymerase, but has no obvious effect on its transcription.
In addition, ribosome profiling combined with quantitative mass spectrometry and mutation studies have found and confirmed that the P gene and X gene of HBV encode a truncated body, named HpZ/P' and HBxZ.
The production of HpZ/P' depends on HBV.
Splicing at two specific sites of pre-genomic RNA, and this splicing method is the most abundant and most conserved among all splicing methods of HBV pre-genomic RNA.
The translation of HBxZ relies on the ribosome to recognize the conserved start codon within the HBx transcript.
Overexpression of these two genes can significantly inhibit the expression of the three main antigens of HBV, HBc, HBs and HBe, while overexpression of HCV polymerase or an unrelated host gene MAP2K2 has no inhibitory effect.
At the same time, southern blot analysis and animal experiments show that HpZ/P' can inhibit the replication and transcription of the HBV genome.
Using second-generation sequencing and third-generation sequencing to analyze the HBV quasispecies of patients with chronic hepatitis B in the immune tolerance phase or immune activation phase, it was found that the mutant A2446G, which specifically deletes HpZ/P' but does not affect the splicing of HBV pre-genomic RNA, And the mutant G1164A that destroys the EnhI-SL element has a significantly higher proportion of quasispecies in patients in the immune tolerance phase than in the immune activation phase, suggesting that these two mutations may have undergone negative screening by the host immune system.
In mechanism, the researchers found that the host protein SUPV3L1 can promote HBV gene expression, suggesting that it may be a host factor held by HBV.
HpZ/P' can interact with the host's SUPV3L1 protein and inhibit the promotion of SUPV3L1 on HBV gene expression.
In addition, studies have found that HpZ/P' can interact with HBx and affect the epigenetic modification of HBV recombinant cccDNA.
Finally, this study found that SRSF2, a component of the host RNA spliceosome, is down-regulated during HBV replication; overexpression of SRSF2 can promote the splicing-dependent HpZ/P' production of viral pre-genomic RNA.
In conclusion, this study started from the analysis of multi-omics integration and revealed a variety of self-limiting mechanisms in the interaction between the hepatitis B virus and the host.
The discovery of these mechanisms on the one hand helps to understand the biological processes related to HBV infection, but also Laid the foundation for the development of new targeted intervention strategies.
Among them, the SRSF2-HpZ/P' axis seems to constitute another negative feedback regulation loop in the life cycle of the hepatitis B virus.
Therefore, targeting the host spliceosome may represent a new strategy to interfere with the hepatitis B virus-host interaction.
Researcher Hu Ronggui from the Center for Excellence in Molecular Cells of the Chinese Academy of Sciences, Professor Deng Qiang from Fudan University School of Basic Medicine, Professor Zhang Jiming from Huashan Hospital of Fudan University, and Professor Xu Ping from the National Phoenix Center for Protein Sciences and Professor Xu Ping from the Chinese Academy of Medical Sciences are co-corresponding authors.
Postdoctoral fellow from the Center for Molecular Cell Excellence Yuan Shilin, Ph.
D.
Student Liao Guanghong, associate researcher Zhang Menghuan, and Fudan University postdoctoral fellow Zhu Yuanfei are the co-first authors.
Professor Axel Walch and Sun Na from the Helmholtz Research Center in Munich are collaborators.
Special thanks to Academician Han Bin, Researcher Huang Xuehui and Researcher Feng Qi of the Center for Excellence in Molecular Plant Science of the Chinese Academy of Sciences, Peng Chao from the National Protein Center (Shanghai), and Researcher Zhou Hu from the Institute of Materia Medica, Chinese Academy of Sciences for their great help in this research.
This work is also strongly supported by the molecular biology technology platform and the cell analysis technology platform, and has received funding support from the Chinese Academy of Sciences, the National Foundation of China, the Ministry of Science and Technology, and the Shanghai Municipal Science and Technology Commission.
Link to the paper: https://doi.
org/10.
1016/j.
jhep.
2021.
02.
009 is open to reprint this article is open to reprint: just leave a message in this article to inform
At present, the number of chronic hepatitis B virus infections in the world is 350 to 400 million, and 75% of the infected people are Asians.
Liver diseases and liver cancer associated with HBV infection are extremely common in China, causing about 400,000 liver cancer deaths every year.
Unlike the new coronavirus, cases of vertical infection in childhood are the main way for HBV to infect humans.
About 25% of patients infected with hepatitis B virus will develop liver fibrosis or liver cancer in adulthood.
Generally speaking, most adults (about 65%) have basically no obvious symptoms after being infected with HBV.
Finally, the body will clear HBV from the body, suggesting that HBV infection in adults is self-limiting, and its mechanism is unknown.
On April 5th, researcher Hu Ronggui from the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences, Professor Deng Qiang from Fudan University School of Basic Medicine, Professor Zhang Jiming from Huashan Hospital of Fudan University, and Professor Xu Ping from the National Phoenix Center for Protein Science were the co-corresponding authors.
The Journal of Hepatology published a research paper titled: Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection.
The study found that the P gene and X gene of hepatitis B virus (Hepatitis B virus, HBV) each encode a homologous isoform HpZ/P' and HBxZ, which can inhibit HBV replication.
The study also discovered a translation regulatory element located in the HBV enhancer I region.
The research uses transcriptome sequencing technology (RNA-sequencing) combined with ribosome profiling technology (ribosome profiling), combined with quantitative proteomics to systematically analyze the interaction between HBV and the host.
By studying a recently developed 1.
0-fold HBV recombinant cccDNA system, the researchers discovered a translation regulatory element EnhI-SL (stem loop within enhancer I) located in the enhancer I region of the HBV genome.
Cell studies have shown that mutations destroy its stem loop The structure can enhance the expression of reporter gene or HBV polymerase, but has no obvious effect on its transcription.
In addition, ribosome profiling combined with quantitative mass spectrometry and mutation studies have found and confirmed that the P gene and X gene of HBV encode a truncated body, named HpZ/P' and HBxZ.
The production of HpZ/P' depends on HBV.
Splicing at two specific sites of pre-genomic RNA, and this splicing method is the most abundant and most conserved among all splicing methods of HBV pre-genomic RNA.
The translation of HBxZ relies on the ribosome to recognize the conserved start codon within the HBx transcript.
Overexpression of these two genes can significantly inhibit the expression of the three main antigens of HBV, HBc, HBs and HBe, while overexpression of HCV polymerase or an unrelated host gene MAP2K2 has no inhibitory effect.
At the same time, southern blot analysis and animal experiments show that HpZ/P' can inhibit the replication and transcription of the HBV genome.
Using second-generation sequencing and third-generation sequencing to analyze the HBV quasispecies of patients with chronic hepatitis B in the immune tolerance phase or immune activation phase, it was found that the mutant A2446G, which specifically deletes HpZ/P' but does not affect the splicing of HBV pre-genomic RNA, And the mutant G1164A that destroys the EnhI-SL element has a significantly higher proportion of quasispecies in patients in the immune tolerance phase than in the immune activation phase, suggesting that these two mutations may have undergone negative screening by the host immune system.
In mechanism, the researchers found that the host protein SUPV3L1 can promote HBV gene expression, suggesting that it may be a host factor held by HBV.
HpZ/P' can interact with the host's SUPV3L1 protein and inhibit the promotion of SUPV3L1 on HBV gene expression.
In addition, studies have found that HpZ/P' can interact with HBx and affect the epigenetic modification of HBV recombinant cccDNA.
Finally, this study found that SRSF2, a component of the host RNA spliceosome, is down-regulated during HBV replication; overexpression of SRSF2 can promote the splicing-dependent HpZ/P' production of viral pre-genomic RNA.
In conclusion, this study started from the analysis of multi-omics integration and revealed a variety of self-limiting mechanisms in the interaction between the hepatitis B virus and the host.
The discovery of these mechanisms on the one hand helps to understand the biological processes related to HBV infection, but also Laid the foundation for the development of new targeted intervention strategies.
Among them, the SRSF2-HpZ/P' axis seems to constitute another negative feedback regulation loop in the life cycle of the hepatitis B virus.
Therefore, targeting the host spliceosome may represent a new strategy to interfere with the hepatitis B virus-host interaction.
Researcher Hu Ronggui from the Center for Excellence in Molecular Cells of the Chinese Academy of Sciences, Professor Deng Qiang from Fudan University School of Basic Medicine, Professor Zhang Jiming from Huashan Hospital of Fudan University, and Professor Xu Ping from the National Phoenix Center for Protein Sciences and Professor Xu Ping from the Chinese Academy of Medical Sciences are co-corresponding authors.
Postdoctoral fellow from the Center for Molecular Cell Excellence Yuan Shilin, Ph.
D.
Student Liao Guanghong, associate researcher Zhang Menghuan, and Fudan University postdoctoral fellow Zhu Yuanfei are the co-first authors.
Professor Axel Walch and Sun Na from the Helmholtz Research Center in Munich are collaborators.
Special thanks to Academician Han Bin, Researcher Huang Xuehui and Researcher Feng Qi of the Center for Excellence in Molecular Plant Science of the Chinese Academy of Sciences, Peng Chao from the National Protein Center (Shanghai), and Researcher Zhou Hu from the Institute of Materia Medica, Chinese Academy of Sciences for their great help in this research.
This work is also strongly supported by the molecular biology technology platform and the cell analysis technology platform, and has received funding support from the Chinese Academy of Sciences, the National Foundation of China, the Ministry of Science and Technology, and the Shanghai Municipal Science and Technology Commission.
Link to the paper: https://doi.
org/10.
1016/j.
jhep.
2021.
02.
009 is open to reprint this article is open to reprint: just leave a message in this article to inform
