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The N-terminal region of influenza virus polymerase PB1 adjacent to the PA binding site is involved in replication but not transcription of the viral genome.

ABSTRACT: The influenza virus genome forms viral ribonucleoprotein (vRNP) complexes with nucleoprotein and viral RNA-dependent RNA polymerases (RdRp), PB1, PB2, and PA subunits. The vRNP complex catalyzes both genome replication and transcription reactions. PB1 contains the motifs highly conserved among RdRps and functions as a catalytic subunit of RdRp. The N-terminal region of PB1 between amino acid (a.a.) positions 1-83 contains both putative vRNA and cRNA promoter binding sites and a PA binding site. However, except for the PA binding site, the crystal structure and the function of the N-terminal region of PB1 are poorly understood. Here, we have examined the functional structure of the N-terminal region of PB1. The regions between a.a. positions 1-50 are highly conserved between influenza A and B viruses, but amino acids at positions 16, 27, and 44 are different between two viruses. To elucidate the functional importance of these amino acids in replication and transcription of the viral genome, we generated viruses containing mutations at these positions by reverse genetics and examined replication and transcription activities of these mutants. We found that a.a. positions 27 and 44 are responsible for the viral replication activity but not transcription activity.

SUBMITTER: Binh NT

PROVIDER: S-EPMC3866587 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The N-terminal region of influenza virus polymerase PB1 adjacent to the PA binding site is involved in replication but not transcription of the viral genome.

Binh Nguyen Trong NT Wakai Chitose C Kawaguchi Atsushi A Nagata Kyosuke K

Frontiers in microbiology 20131218

The influenza virus genome forms viral ribonucleoprotein (vRNP) complexes with nucleoprotein and viral RNA-dependent RNA polymerases (RdRp), PB1, PB2, and PA subunits. The vRNP complex catalyzes both genome replication and transcription reactions. PB1 contains the motifs highly conserved among RdRps and functions as a catalytic subunit of RdRp. The N-terminal region of PB1 between amino acid (a.a.) positions 1-83 contains both putative vRNA and cRNA promoter binding sites and a PA binding site. ...[more]

PMID: 24391632

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Project description:Highly pathogenic influenza A viruses (IAV) from avian hosts were first reported to directly infect humans 20 years ago. However, such infections are rare events, and our understanding of factors promoting or restricting zoonotic transmission is still limited. One accessory protein of IAV, PB1-F2, was associated with pathogenicity of pandemic and zoonotic IAV. This short (90-amino-acid) peptide does not harbor an enzymatic function. We thus identified host factors interacting with H5N1 PB1-F2, which could explain its importance for virulence. PB1-F2 binds to HCLS1-associated protein X1 (HAX-1), a recently identified host restriction factor of the PA subunit of IAV polymerase complexes. We demonstrate that the PA of a mammal-adapted H1N1 IAV is resistant to HAX-1 imposed restriction, while the PA of an avian-origin H5N1 IAV remains sensitive. We also showed HAX-1 sensitivity for PAs of A/Brevig Mission/1/1918 (H1N1) and A/Shanghai/1/2013 (H7N9), two avian-origin zoonotic IAV. Inhibition of H5N1 polymerase by HAX-1 can be alleviated by its PB1-F2 through direct competition. Accordingly, replication of PB1-F2-deficient H5N1 IAV is attenuated in the presence of large amounts of HAX-1. Mammal-adapted H1N1 and H3N2 viruses do not display this dependence on PB1-F2 for efficient replication in the presence of HAX-1. We propose that PB1-F2 plays a key role in zoonotic transmission of avian H5N1 IAV into humans.IMPORTANCE Aquatic and shore birds are the natural reservoir of influenza A viruses from which the virus can jump into a variety of bird and mammal host species, including humans. H5N1 influenza viruses are a good model for this process. They pose an ongoing threat to human and animal health due to their high mortality rates. However, it is currently unclear what restricts these interspecies jumps on the host side or what promotes them on the virus side. Here we show that a short viral peptide, PB1-F2, helps H5N1 bird influenza viruses to overcome a human restriction factor of the viral polymerase complex HAX-1. Interestingly, we found that human influenza A virus polymerase complexes are already adapted to HAX-1 and do not require this function of PB1-F2. We thus propose that a functional full-length PB1-F2 supports direct transmission of bird viruses into humans.

Dataset Information

The N-terminal region of influenza virus polymerase PB1 adjacent to the PA binding site is involved in replication but not transcription of the viral genome.

Publications

The N-terminal region of influenza virus polymerase PB1 adjacent to the PA binding site is involved in replication but not transcription of the viral genome.

Similar Datasets

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