Inefficient splicing of segment 7 and 8 mRNAs is an inherent property of influenza virus A/Brevig Mission/1918/1 (H1N1) that causes elevated expression of NS1 protein

Winquist, Ellenor Backström; Abdurahman, Samir; Tranell, Anna; Lindström, Sofia; Tingsborg, Susanne; Schwartz, Stefan

doi:10.1016/j.virol.2011.10.004

Cited by 20 publications

(19 citation statements)

References 55 publications

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“…The data obtained demonstrated that although the amount of NS2 produced by the NS2-shifted constructs was decreased by half compared to that produced by the parental NS gene segments (Fig. 6A, compare the amounts of NS2 displayed by the different constructs, and B, compare bars 1 and 2 with bars 5 and 6), the amount of NS2 should still be sufficient to ensure virus survival because similar ratios of NS2 to NS1 are known to be produced by some human influenza viruses (58). Furthermore, no substantial difference in NS2 synthesis between the shifted constructs was observed (Fig.…”

Section: Ns1 Sumoylation Affects Viral Growth In Ifn-competent and Ifmentioning

confidence: 95%

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Santos

Pal

Chacon

et al. 2013

J Virol

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Our pioneering studies on the interplay between the small ubiquitin-like modifier (SUMO) and influenza A virus identified the nonstructural protein NS1 as the first known SUMO target of influenza virus and one of the most abundantly SUMOylated influenza virus proteins. Here, we further characterize the role of SUMOylation for the A/Puerto Rico/8/1934 (PR8) NS1 protein, demonstrating that NS1 is SUMOylated not only by SUMO1 but also by SUMO2/3 and mapping the main SUMOylation sites in NS1 to residues K219 and K70. Furthermore, by using SUMOylatable and non-SUMOylatable forms of NS1 and an NS1-specific artificial SUMO ligase (ASL) that increases NS1 SUMOylation ϳ4-fold, we demonstrate that SUMOylation does not affect the stability or cellular localization of PR8 NS1. However, NS1's ability to be SUMOylated appears to affect virus multiplication, as indicated by the delayed growth of a virus expressing the non-SUMOylatable form of NS1 in the interferon (IFN)-competent MDCK cell line. Remarkably, while a non-SUMOylatable form of NS1 exhibited a substantially diminished ability to neutralize IFN production, increasing NS1 SUMOylation beyond its normal levels also exerted a negative effect on its IFN-blocking function. This observation indicates the existence of an optimal level of NS1 SUMOylation that allows NS1 to achieve maximal activity and suggests that the limited amount of SUMOylation normally observed for most SUMO targets may correspond to an optimal level that maximizes the contribution of SUMOylation to protein function. Finally, protein cross-linking data suggest that SUMOylation may affect NS1 function by regulating the abundance of NS1 dimers and trimers in the cell.

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Section: Ns1 Sumoylation Affects Viral Growth In Ifn-competent and Ifmentioning

confidence: 95%

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Santos

Pal

Chacon

et al. 2013

J Virol

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“…Recent studies have hypothesized that the splicing efficiency of the M and NS segments of IAV could be a determinant in their ability to replicate or to adapt to a new host, denoting an important concern for pathogenicity (79, 96). Chua and colleagues have recently demonstrated that suboptimal splicing of the NS segment plays a role as a “molecular timer” that coordinates the timing of infection (79).…”

Section: Is Splicing a Key Determinant For Viral Replication Host Ramentioning

confidence: 99%

“…Chua and colleagues have recently demonstrated that suboptimal splicing of the NS segment plays a role as a “molecular timer” that coordinates the timing of infection (79). Moreover, results obtained by Backström Winquist and colleagues have shown that the splicing efficiency of M and NS mRNAs varies between different influenza viruses (96). For example, the NS segment from A/Brevig Mission/1919/1 (H1N1) has been shown to be inefficiently spliced compared to those of other influenza viruses, possibly due to the differential binding properties of cellular splicing factors (e.g., SR proteins), resulting in the production of higher levels of functional NS1.…”

Section: Is Splicing a Key Determinant For Viral Replication Host Ramentioning

confidence: 99%

“…For example, the NS segment from A/Brevig Mission/1919/1 (H1N1) has been shown to be inefficiently spliced compared to those of other influenza viruses, possibly due to the differential binding properties of cellular splicing factors (e.g., SR proteins), resulting in the production of higher levels of functional NS1. The authors hypothesized that this could have contributed to the pathogenicity of the 1918 pandemic Spanish influenza virus (96). Another argument in favor of the importance of splicing strategy for influenza virus fitness was brought forward by Selman and colleagues with the description of NS3 protein expression in response to mouse adaptation (43).…”

Section: Is Splicing a Key Determinant For Viral Replication Host Ramentioning

confidence: 99%

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Influenza Viruses and mRNA Splicing: Doing More with Less

Dubois

Terrier

Rosa‐Calatrava

2014

mBio

129

132

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During their nuclear replication stage, influenza viruses hijack the host splicing machinery to process some of their RNA segments, the M and NS segments. In this review, we provide an overview of the current knowledge gathered on this interplay between influenza viruses and the cellular spliceosome, with a particular focus on influenza A viruses (IAV). These viruses have developed accurate regulation mechanisms to reassign the host spliceosome to alter host cellular expression and enable an optimal expression of specific spliced viral products throughout infection. Moreover, IAV segments undergoing splicing display high levels of similarity with human consensus splice sites and their viral transcripts show noteworthy secondary structures. Sequence alignments and consensus analyses, along with recently published studies, suggest both conservation and evolution of viral splice site sequences and structure for improved adaptation to the host. Altogether, these results emphasize the ability of IAV to be well adapted to the host’s splicing machinery, and further investigations may contribute to a better understanding of splicing regulation with regard to viral replication, host range, and pathogenesis.

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“…The NS1 and NEP proteins play different roles during virus infection and regulation of splicing of mRNA to favour either NS1 or NEP could significantly affect virus replication efficiency. Indeed, it is suggested that inefficient splicing of NS mRNAs of the pandemic A/Brevig Mission/1918/1 (H1N1) virus resulted in higher levels of the NS1 protein, contributing to its pathogenic properties19. NEP is required for coordination of viral ribonucleoprotein (RNP) nuclear export in the later stage of infection and it is suggested that virus adapts to utilize a poor 5′-splice site to allow slow expression of NEP early in virus infection20.…”

mentioning

confidence: 99%

An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells

et al. 2017

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Influenza virus utilizes host splicing machinery to process viral mRNAs expressed from both M and NS segments. Through genetic analysis and functional characterization, we here show that the NS segment of H7N9 virus contains a unique G540A substitution, located within a previously undefined exonic splicing enhancer (ESE) motif present in the NEP mRNA of influenza A viruses. G540A supports virus replication in mammalian cells while retaining replication ability in avian cells. Host splicing regulator, SF2, interacts with this ESE to regulate splicing of NEP/NS1 mRNA and G540A substitution affects SF2–ESE interaction. The NS1 protein directly interacts with SF2 in the nucleus and modulates splicing of NS mRNAs during virus replication. We demonstrate that splicing of NEP/NS1 mRNA is regulated through a cis NEP-ESE motif and suggest a unique NEP-ESE may contribute to provide H7N9 virus with the ability to both circulate efficiently in avian hosts and replicate in mammalian cells.

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Inefficient splicing of segment 7 and 8 mRNAs is an inherent property of influenza virus A/Brevig Mission/1918/1 (H1N1) that causes elevated expression of NS1 protein

Cited by 20 publications

References 55 publications

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

SUMOylation Affects the Interferon Blocking Activity of the Influenza A Nonstructural Protein NS1 without Affecting Its Stability or Cellular Localization

Influenza Viruses and mRNA Splicing: Doing More with Less

An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells

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