Role of influenza A virus NP acetylation on viral growth and replication

Giese, Sebastian; Ciminski, Kevin; Bolte, Hardin; Moreira, Étori Aguiar; Lakdawala, Seema S.; Hu, Zehan; David, Quinnlan; Kolesnikova, Larissa; Götz, Veronika; Zhao, Yongxu; Dengjel, Jörn; Chin, Y. Eugene; Xu, Ke; Schwemmle, Martin

doi:10.1038/s41467-017-01112-3

Cited by 51 publications

(53 citation statements)

References 43 publications

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“…Acetylation enhances the enzymatic activity of the HIV integrase and increases its affinity for DNA (Cereseto et al, 2005). More recently, it was shown that acetylation of highly conserved lysine residues might regulate specific functions of nucleoprotein in the viral life cycle of influenza A viruses, including viral replication (Giese et al, 2017). Lastly, we have found that the mechanisms by which human fragments and duplications increase the net load differ.…”

Section: Discussionmentioning

confidence: 88%

Insertions and Duplications in the Polyproline Region of the Hepatitis E Virus

et al. 2020

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Recombinant strains of hepatitis E virus (HEV) with insertions of human genomic fragments or HEV sequence duplications in the sequence encoding the polyproline region (PPR) were previously described in chronically infected patients. Such genomic rearrangements confer a replicative advantage in vitro but little is known about their frequency, location, or origin. As the sequences of only a few virus genomes are available, we analyzed the complete genomes of 114 HEV genotype 3 strains from immunocompromised (n = 85) and immunocompetent (n = 29) patients using the single molecular real-time sequencing method to determine the frequency, location, and origin of inserted genomic fragments, plus the proportions of variants with genomic rearrangements in each virus quasispecies. We also examined the amino acid compositions and post-translational modifications conferred by these rearrangements by comparing them to sequences without human gene insertions or HEV gene duplications. We found genomic rearrangements in 7/114 (6.1%) complete genome sequences (4 HEV-3f, 1 HEV-3e, 1 HEV-3 h, and 1 HEV-3chi-new), all from immunocompromised patients, and 3/7 were found at the acute phase of infection. Six of the seven patients harbored virus-host recombinant variants, including one patient with two different recombinant variants. We also detected three recombinant variants with genome duplications of the PPR or PPR + X domains in a single patient. All the genomic rearrangements (seven human fragment insertions of varying origins and three HEV genome duplications) occurred in the PPR. The sequences with genomic rearrangements had specific characteristics: increased net load ( p < 0.001) and more ubiquitination ( p < 0.001), phosphorylation ( p < 0.001), and acetylation ( p < 0.001) sites. The human fragment insertions and HEV genome duplications had slightly different characteristics. We believe this is the first description of HEV strains with genomic rearrangements in patients at the acute phase of infection; perhaps these strains are directly transmitted. Clearly, genomic rearrangements produce a greater net load with duplications and insertions having different features. Further studies are needed to clarify the mechanisms by which such modifications influence HEV replication.

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Section: Discussionmentioning

confidence: 88%

Insertions and Duplications in the Polyproline Region of the Hepatitis E Virus

et al. 2020

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“…Acetylation is an important post-translational modification in eukaryotes, but the occurrence and function of acetylation in influenza viral proteins remain largely unclear. Giese et al reported that acetylation of 77 K, 113 K, and 229 K of NP proteins is important for virus polymerase activity and replication [27]. In the present study, we identified and characterized the acetylation of K108 in the NS1 protein, and the deacetylation of K108Q affected viral replication in cells at 36 and 48 hpi.…”

Section: Discussionmentioning

confidence: 52%

“…Acetylation has been found in multiple proteins of influenza viruses. Acetylation was identified in the NP protein of influenza virus, and deacetylation of the NP protein prevented the virus from assembling functional virus particles [27]. A histone-like sequence (histone mimic) was identified in the NS1 protein of influenza A H3N2, which contributes to suppression of the antiviral response [28].…”

Section: Introductionmentioning

confidence: 99%

Acetylation at K108 of the NS1 protein is important for the replication and virulence of influenza virus

et al. 2020

Vet Res

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Non-structural protein 1 (NS1) of influenza virus is a multifunctional protein that plays an important role in virus replication and virulence. In this study, an acetylation modification was identified at the K108 residue of the NS1 protein of H1N1 influenza virus. To further explore the function of the K108 acetylation modification of the NS1 protein, a deacetylation-mimic mutation (K108R) and a constant acetylation-mimic mutation (K108Q) were introduced into the NS1 protein in the background of A/WSN/1933 H1N1 (WSN), resulting in two mutant viruses (WSN-NS1-108R and WSN-NS1-108Q). In vitro and mouse studies showed that the deacetylation-mimic mutation K108R in the NS1 protein attenuated the replication and virulence of WSN-NS1-108R, while the constant acetylation-mimic mutant virus WSN-NS1-108Q showed similar replication and pathogenicity as the wild-type WSN virus (WSN-wt). The results indicated that acetylation at K108 of the NS1 protein has an important role in the replication and virulence of influenza virus. To further explore the potential mechanism, the type I interferon (IFN-I) antagonistic activity of the three NS1 proteins (NS1-108Q, NS1-108R, and NS1-wt) was compared in cells, which showed that the K108R mutation significantly attenuated the IFN-β antagonistic activity of the NS1 protein compared with NS1-wt and NS1-108Q. Both NS1-wt and NS1-108Q inhibited the IFN-β response activated by RIG-I CARD domain, MAVS, TBK1, and IRF3 more efficiently than the NS1-108R protein in cells. Taken together, the results indicated that acetylation at NS1 K108 is important for the IFN antagonistic activity of the NS1 protein and virulence of the influenza virus. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…As a major component of the vRNP complex, NP mediates the nuclear import and export of the vRNP complex in the virus life cycle, and the function of NP is affected by various modifications and host factors (36,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58). Previous studies identified several amino acids in NP that are involved in the NP posttranslational modifications of ubiquitination, phosphorylation, sumoylation, and acetylation, thereby affecting viral replication or virulence in vitro or in vivo (51, 52, 54, 55).…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Mutations A286V and T437M in the Nucleoprotein Attenuate H7N9 Viruses in Mice

Zhang

Shi

et al. 2020

J Virol

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The low-pathogenic H7N9 influenza viruses that emerged in 2013 acquired an insertion of four amino acids in their hemagglutinin cleavage site and thereby became highly pathogenic to chickens in 2017. Previous studies indicated that these highly pathogenic H7N9 viruses are virulent in chickens but have distinct pathotypes in mice. A/chicken/Guangdong/SD098/2017 (CK/SD098) is avirulent, with a 50% mouse lethal dose (MLD50) of >7.5 log10 50% egg infectious dose (EID50), whereas A/chicken/Hunan/S1220/2017 (CK/S1220) is virulent in mice, with an MLD50 of 3.2 log10 EID50. In this study, we explored the genetic determinants that contribute to the difference in virulence between these two H7N9 viruses by generating a series of reassortants and mutants in the CK/S1220 virus background and testing their virulence in mice. We found that the reassortant CK/1220-SD098-NP, carrying the nucleoprotein (NP) of CK/SD098, was avirulent in mice, with an MLD50 of >107.5 EID50. The NPs of these two viruses differ by two amino acids, at positions 286 and 437. We further demonstrated that the amino acid mutations A286V and T437M of NP independently slowed the process of NP import to and export from the nucleus and thus jointly impaired the viral life cycle and attenuated the virulence of these H7N9 viruses in mice. Our study identified new virulence determinants in NP and provided novel targets for the development of live attenuated vaccines and antiviral drugs against influenza viruses. IMPORTANCE The H7N9 influenza viruses that emerged in China in 2013 have caused over 1,500 human infections, with a mortality rate of nearly 40%. The viruses were initially low pathogenic but became highly pathogenic in chickens at the beginning of 2017 and caused severe disease outbreaks in poultry. Several studies suggested that the highly pathogenic H7N9 viruses have increased virulence in mammals; however, the genetic basis of the virulence of H7N9 viruses in mammals is not fully understood. Here, we found that two amino acids, 286A and 437T, in NP are prerequisites for the virulence of H7N9 viruses in mice and the mutations A286V and T437M collectively eliminate the virulence of H7N9 viruses in mice. Our study further demonstrated that the virulence of influenza viruses is a polygenic trait, and the newly identified virulence-related residues in NP may provide new targets for attenuated influenza vaccine and antiviral drug development.

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Role of influenza A virus NP acetylation on viral growth and replication

Cited by 51 publications

References 43 publications

Insertions and Duplications in the Polyproline Region of the Hepatitis E Virus

Insertions and Duplications in the Polyproline Region of the Hepatitis E Virus

Acetylation at K108 of the NS1 protein is important for the replication and virulence of influenza virus

Amino Acid Mutations A286V and T437M in the Nucleoprotein Attenuate H7N9 Viruses in Mice

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