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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 are Asians.
Liver diseases and liver cancer related to HBV infection in China are extremely common, causing about 400,000 liver cancer deaths each year.
Unlike the new coronavirus (COVID-19), 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 5, 2021, the Center for Excellence in Molecular and Cellular Sciences of the Chinese Academy of Sciences (Institute of Biochemistry and Cell Biology)-Hangzhou Advanced Research Institute Protein Homeostasis and Disease Research Team published the latest research results Translatomic online in the Journal of Hepatology 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; in addition, the study also found one The translational regulatory elements located in the HBV enhancer I region.
This study 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, ribosomal 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 the pre-HBV The splicing of two specific sites of genomic RNA, and this splicing method is the most abundant and most conservative of 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 mutants that specifically deleted HpZ/P' but did not affect the splicing of HBV pre-genomic RNA The proportion of A2446G and the mutant G1164A that destroys EnhI-SL elements in the quasispecies of patients in the immune tolerance phase is significantly higher than that 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 multi-omics integrated analysis and revealed a variety of self-limiting mechanisms in the interaction between 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, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Professor Deng Qiang, School of Basic Medicine/Key Laboratory of Medical Molecular Virology (MOE&MOH), Fudan University, Professor Zhang Jiming, Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, and National Phoenix Center for Protein Sciences (Beijing) )/Proteomics and New Drug Research and Development Institute of Chinese Academy of Medical Sciences/Professor Xu Ping from Beijing Institutes of Biological Sciences is the co-corresponding author, Yuan Shilin, postdoctoral fellow at the Center for Excellence in Molecular Cell Science, PhD student Liao Guanghong and associate researcher Zhang Menghuan, and Fudan University postdoctoral fellow Zhu Yuanfei As the co-first author.
Professor Axel Walch and Sun Na from the Helmholtz Research Center in Munich are collaborators.
Article link: https://authors.
elsevier.
com/c/1cs7xcOnAJ8c6 Platemaker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, and the author owns all legal rights.
Rights, offenders must be investigated.
At present, the number of chronic hepatitis B virus infections in the world is 350 to 400 million, and 75% of the infected are Asians.
Liver diseases and liver cancer related to HBV infection in China are extremely common, causing about 400,000 liver cancer deaths each year.
Unlike the new coronavirus (COVID-19), 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 5, 2021, the Center for Excellence in Molecular and Cellular Sciences of the Chinese Academy of Sciences (Institute of Biochemistry and Cell Biology)-Hangzhou Advanced Research Institute Protein Homeostasis and Disease Research Team published the latest research results Translatomic online in the Journal of Hepatology 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; in addition, the study also found one The translational regulatory elements located in the HBV enhancer I region.
This study 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, ribosomal 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 the pre-HBV The splicing of two specific sites of genomic RNA, and this splicing method is the most abundant and most conservative of 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 mutants that specifically deleted HpZ/P' but did not affect the splicing of HBV pre-genomic RNA The proportion of A2446G and the mutant G1164A that destroys EnhI-SL elements in the quasispecies of patients in the immune tolerance phase is significantly higher than that 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 multi-omics integrated analysis and revealed a variety of self-limiting mechanisms in the interaction between 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, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Professor Deng Qiang, School of Basic Medicine/Key Laboratory of Medical Molecular Virology (MOE&MOH), Fudan University, Professor Zhang Jiming, Department of Infectious Diseases, Huashan Hospital, Shanghai Medical College, Fudan University, and National Phoenix Center for Protein Sciences (Beijing) )/Proteomics and New Drug Research and Development Institute of Chinese Academy of Medical Sciences/Professor Xu Ping from Beijing Institutes of Biological Sciences is the co-corresponding author, Yuan Shilin, postdoctoral fellow at the Center for Excellence in Molecular Cell Science, PhD student Liao Guanghong and associate researcher Zhang Menghuan, and Fudan University postdoctoral fellow Zhu Yuanfei As the co-first author.
Professor Axel Walch and Sun Na from the Helmholtz Research Center in Munich are collaborators.
Article link: https://authors.
elsevier.
com/c/1cs7xcOnAJ8c6 Platemaker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, and the author owns all legal rights.
Rights, offenders must be investigated.
