Hepatitis B virus X protein recruits methyltransferases to affect cotranscriptional N6-methyladenosine modification of viral/host RNAs

Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m A) modification of cellular and viral RNAs is the most prevalent internal modification that occurs cotranscriptionally. Previously, we reported the dual functiona...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 3
Main Authors: Kim, Geon-Woo, Siddiqui, Aleem
Format: Journal Article
Language:English
Published: United States 19.01.2021
Subjects:
Adenosine - analogs & derivatives
Adenosine - genetics
Hep G2 Cells
Hepatitis B virus - genetics
Hepatitis B virus - pathogenicity
Hepatitis B, Chronic - genetics
Hepatitis B, Chronic - virology
Host-Pathogen Interactions - genetics
Humans
Methyltransferases - genetics
PTEN Phosphohydrolase - genetics
RNA Processing, Post-Transcriptional - genetics
RNA, Viral - genetics
Trans-Activators - genetics
Viral Regulatory and Accessory Proteins - genetics
Virus Replication - genetics
cotranscriptional modification
hepatitis B virus X protein
METTL3/14
N6-methyladenosine modification
hepatitis B virus
ISSN:1091-6490, 1091-6490
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Abstract Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m A) modification of cellular and viral RNAs is the most prevalent internal modification that occurs cotranscriptionally. Previously, we reported the dual functional role of m A modification of HBV transcripts in the viral life cycle. Here, we show that viral HBV X (HBx) protein is responsible for the m A modifications of viral transcripts. HBV genomes defective in HBx failed to induce m A modifications of HBV RNAs during infection/transfection, while ectopic expression of HBx restores m A modifications of the viral RNAs but not the mutant HBx carrying the nuclear export signal. Using chromatin immunoprecipitation assays, we provide evidence that HBx and m A methyltransferase complexes are localized on the HBV minichromosome to achieve cotranscriptional m A modification of viral RNAs. HBx interacts with METTL3 and 14 to carry out methylation activity and also modestly stimulates their nuclear import. This role of HBx in mediating m A modification also extends to host phosphatase and tensin homolog (PTEN) mRNA. This study provides insight into how a viral protein recruits RNA methylation machinery to m A-modify RNAs.
AbstractList Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m6A) modification of cellular and viral RNAs is the most prevalent internal modification that occurs cotranscriptionally. Previously, we reported the dual functional role of m6A modification of HBV transcripts in the viral life cycle. Here, we show that viral HBV X (HBx) protein is responsible for the m6A modifications of viral transcripts. HBV genomes defective in HBx failed to induce m6A modifications of HBV RNAs during infection/transfection, while ectopic expression of HBx restores m6A modifications of the viral RNAs but not the mutant HBx carrying the nuclear export signal. Using chromatin immunoprecipitation assays, we provide evidence that HBx and m6A methyltransferase complexes are localized on the HBV minichromosome to achieve cotranscriptional m6A modification of viral RNAs. HBx interacts with METTL3 and 14 to carry out methylation activity and also modestly stimulates their nuclear import. This role of HBx in mediating m6A modification also extends to host phosphatase and tensin homolog (PTEN) mRNA. This study provides insight into how a viral protein recruits RNA methylation machinery to m6A-modify RNAs.Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m6A) modification of cellular and viral RNAs is the most prevalent internal modification that occurs cotranscriptionally. Previously, we reported the dual functional role of m6A modification of HBV transcripts in the viral life cycle. Here, we show that viral HBV X (HBx) protein is responsible for the m6A modifications of viral transcripts. HBV genomes defective in HBx failed to induce m6A modifications of HBV RNAs during infection/transfection, while ectopic expression of HBx restores m6A modifications of the viral RNAs but not the mutant HBx carrying the nuclear export signal. Using chromatin immunoprecipitation assays, we provide evidence that HBx and m6A methyltransferase complexes are localized on the HBV minichromosome to achieve cotranscriptional m6A modification of viral RNAs. HBx interacts with METTL3 and 14 to carry out methylation activity and also modestly stimulates their nuclear import. This role of HBx in mediating m6A modification also extends to host phosphatase and tensin homolog (PTEN) mRNA. This study provides insight into how a viral protein recruits RNA methylation machinery to m6A-modify RNAs.
Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m A) modification of cellular and viral RNAs is the most prevalent internal modification that occurs cotranscriptionally. Previously, we reported the dual functional role of m A modification of HBV transcripts in the viral life cycle. Here, we show that viral HBV X (HBx) protein is responsible for the m A modifications of viral transcripts. HBV genomes defective in HBx failed to induce m A modifications of HBV RNAs during infection/transfection, while ectopic expression of HBx restores m A modifications of the viral RNAs but not the mutant HBx carrying the nuclear export signal. Using chromatin immunoprecipitation assays, we provide evidence that HBx and m A methyltransferase complexes are localized on the HBV minichromosome to achieve cotranscriptional m A modification of viral RNAs. HBx interacts with METTL3 and 14 to carry out methylation activity and also modestly stimulates their nuclear import. This role of HBx in mediating m A modification also extends to host phosphatase and tensin homolog (PTEN) mRNA. This study provides insight into how a viral protein recruits RNA methylation machinery to m A-modify RNAs.
Author Siddiqui, Aleem
Kim, Geon-Woo
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  organization: Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, La Jolla, CA 92093 asiddiqui@ucsd.edu
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hepatitis B virus X protein
METTL3/14
N6-methyladenosine modification
hepatitis B virus
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Snippet Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m A) modification of...
Chronic hepatitis B virus (HBV) infections are one of the leading causes of cirrhosis and hepatocellular carcinoma. N6-methyladenosine (m6A) modification of...
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SubjectTerms Adenosine - analogs & derivatives
Adenosine - genetics
Hep G2 Cells
Hepatitis B virus - genetics
Hepatitis B virus - pathogenicity
Hepatitis B, Chronic - genetics
Hepatitis B, Chronic - virology
Host-Pathogen Interactions - genetics
Humans
Methyltransferases - genetics
PTEN Phosphohydrolase - genetics
RNA Processing, Post-Transcriptional - genetics
RNA, Viral - genetics
Trans-Activators - genetics
Viral Regulatory and Accessory Proteins - genetics
Virus Replication - genetics
Title Hepatitis B virus X protein recruits methyltransferases to affect cotranscriptional N6-methyladenosine modification of viral/host RNAs
URI https://www.ncbi.nlm.nih.gov/pubmed/33397803
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