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PB1 F2 - properties

G

Ganseerpel

Advisory Board, Senior Moderator
Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice.
Zamarin D, Ortigoza MB, Palese P.
J Virol. 2006 Aug;80(16):7976-83.
Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029, USA.
The influenza virus PB1-F2 protein is a novel protein previously shown to be involved in induction of cell death. Here we characterize the expression and the function of the protein within the context of influenza viral infection in tissue culture and a mouse model. We show that the C-terminal region of the protein can be expressed from a downstream initiation codon and is capable of interaction with the full-length protein. Using this knowledge, we generated influenza viruses knocked out for the expression of PB1-F2 protein and its downstream truncation products. Knocking out the PB1-F2 protein had no effect on viral replication in tissue culture but diminished virus pathogenicity and mortality in mice. The viruses replicated to similar levels in mouse lungs by day 3 postinfection, suggesting that the knockout did not impair viral replication. However, while the PB1-F2 knockout viruses were cleared after day 5, the wild-type viruses were detectable in mouse lungs until day 7, implying that expression of PB1-F2 resulted in delayed clearance of the viruses by the host immune system. Based on our findings and on the fact that the PB1 genomic segment was always newly introduced into some pandemic influenza viruses of the last century, we speculate that the PB1-F2 protein plays an important role in pathogenesis of influenza virus infection and may be an important contributor to pathogenicity of pandemic influenza viruses.
Publication Types:

Full text :http://jvi.asm.org/cgi/content/full/80/16/7976?view=long&pmid=16873254
 
Re: PB1 F2 - properties

that could mean that the CFR might go down in a pandemic since the
less virulent virus can replicate just as well
 
Re: PB1 F2 - properties

[SIZE=-1]Originally published In Press as doi:10.1074/jbc.M606494200 on October 19, 2006[/SIZE] [SIZE=-1]J. Biol. Chem., Vol. 282, Issue 1, 353-363, January 5, 2007[/SIZE]
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Structural Characterization and Oligomerization of PB1-F2, a Proapoptotic Influenza A Virus Protein<sup>*</sup><sup>
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</sup>

<nobr>Karsten Bruns<sup>
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</sup><sup>
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</sup><sup>?</sup><sup>1</sup></nobr>, <nobr>Nicole Studtrucker<sup>
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</sup><sup>1</sup></nobr>, <nobr>Alok Sharma<sup>
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</sup><sup>?</sup></nobr>, <nobr>Torgils Fossen<sup>?</sup><sup>||</sup></nobr>, <nobr>David Mitzner<sup>
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</sup></nobr>, <nobr>Andr? Eissmann<sup>
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</sup></nobr>, <nobr>Uwe Tessmer<sup>
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</sup></nobr>, <nobr>Ren? R?der<sup>
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</sup><sup>**</sup></nobr>, <nobr>Peter Henklein<sup>**</sup></nobr>, <nobr>Victor Wray<sup>?</sup></nobr>, and <nobr>Ulrich Schubert<sup>
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</sup><sup>2</sup></nobr> From the <sup>
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</sup>Institute of Clinical and Molecular Virology, University of Erlangen-N?rnberg, Erlangen D-91054, Germany, <sup>
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</sup>Heinrich-Pette-Institute, Hamburg D-20251, Germany, the <sup>?</sup>Department of Structural Biology, Helmholtz Centre for Infection Research, Braunschweig D-38124, Germany, the <sup>||</sup>Department of Chemistry, University of Bergen, N-5007 Bergen, Norway, and the <sup>**</sup>Institute of Biochemistry, Humboldt University, Berlin D-10115, Germany
<!-- ABS --> Recently, a novel 87-amino acid influenza A virus protein with<sup> </sup>proapoptotic properties, PB1-F2, has been reported that originates<sup> </sup>from an alternative reading frame in the PB1 polymerase gene<sup> </sup>and is encoded in most known human influenza A virus isolates.<sup> </sup>Here we characterize the molecular structure of a biologically<sup> </sup>active synthetic version of the protein (sPB1-F2). Western blot<sup> </sup>analysis, chemical cross-linking, and NMR spectroscopy afforded<sup> </sup>direct evidence of the inherent tendency of sPB1-F2 to undergo<sup> </sup>oligomerization mediated by two distinct domains located in<sup> </sup>the N and C termini, respectively. CD and <sup>1</sup>H NMR spectroscopic<sup> </sup>analyses indicate that the stability of structured regions in<sup> </sup>the molecule clearly depends upon the hydrophobicity of the<sup> </sup>solvent. In aqueous solutions, the behavior of sPB1-F2 is typical<sup> </sup>of a largely random coil peptide that, however, adopts
alpha.gif
-helical<sup> </sup>structure upon the addition of membrane mimetics. <sup>1</sup>H NMR analysis<sup> </sup>of three overlapping peptides afforded, for the first time,<sup> </sup>direct experimental evidence of the presence of a C-terminal<sup> </sup>region with strong
alpha.gif
-helical propensity comprising amino acid<sup> </sup>residues Ile<sup>55</sup>-Lys<sup>85</sup> connected via an essentially random coil<sup> </sup>structure to a much weaker helix-like region, located in the<sup> </sup>N terminus between residues Trp<sup>9</sup> and Lys<sup>20</sup>. The C-terminal helix<sup> </sup>is not a true amphipathic helix and is more compact than previously<sup> </sup>predicted. It corresponds to a positively charged region previously<sup> </sup>shown to include the mitochondrial targeting sequence of PB1-F2.<sup> </sup>The consequences of the strong oligomerization and helical propensities<sup> </sup>of the molecule are discussed and used to formulate a hypothetical<sup> </sup>model of its interaction with the mitochondrial membrane.<sup> </sup>

<hr align="left" noshade="noshade" size="1" width="50%">
Received for publication, July 7, 2006 , and in revised form, October 11, 2006.
<!-- null --> The atomic coordinates and structure factors (code 2HN8) have<sup> </sup>been deposited in the Protein Data Bank, Research Collaboratory<sup> </sup>for Structural Bioinformatics, Rutgers University, New Brunswick,<sup> </sup>NJ (http://www.rcsb.org/).<sup> </sup>
<!-- null --> <sup>*</sup> This work was supported by a grant from the research network<sup> </sup>FORINGEN, funded by the State of Bavaria, Germany, by German<sup> </sup>Human Genome Research Project Grant IE-S08T06, and by German<sup> </sup>Research Council Grants SFB 466-A11, SFB 643-A1, and GRKK 1071.<sup> </sup>The costs of publication of this article were defrayed in part<sup> </sup>by the payment of page charges. This article must therefore<sup> </sup>be hereby marked "advertisement" in accordance with 18 U.S.C.<sup> </sup>Section 1734 solely to indicate this fact.<sup> </sup>
<!-- null --> <sup>
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</sup> The on-line version of this article (available at http://www.jbc.org)<sup> </sup>contains supplemental Fig. S1 and Table
 
Re: PB1 F2 - properties

Influenza A virus PB1-F2 gene


Emerging Infectious Diseases, Oct, 2006 by Roland Zell, Andi Krumbholz, Peter Wutzler, Guang-Wu Chen, Shin-Ru Shih

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<!-- no query term? print empty widget --> To the Editor: Recently, Chen and co-workers described the expression of an 11th influenza A virus protein, designated PB1-F2 because this protein is encoded in the +1 open reading frame of the segment-2 RNA (1). Later, Chen et al. presented a preliminary analysis of 336 PB1 sequences from GenBank (2). We have extended the work on PB1-F2 and analyzed 1,864 partial and complete segment-2 sequences deposited in GenBank; these sequences belong to 79 influenza A virus subtypes. In summary, the following 8 observations should receive attention:
First, the size of PB1-F2 polypeptides ranges from 79 to 101 amino acids (aa); most isolates encode versions of either 87 or 90 aa. Because polypeptides of 79 aa are located within mitochondria, their truncation has no effect on the protein function. The frequency of the 79-aa PB1-F2 is [approximately equal to] 5%.
Second, a functional PB1-F2 is expressed by 92% of all segment-2 sequences, i.e., a polypeptide >78 aa. The proportion of intact PB1-F2 varies according to host (humans 90%, swine 76%, other mammals 100%, birds 95%).
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Third, the H1N1 subtype comprises 3 genetic lineages. One clade has 2 branches: 1 branch includes the human viruses, with the pandemic 1918 virus at its root; the other branch includes the classic swine viruses. The third clade represents the European porcine isolates. Although all classic swine sequences have a truncated PB1-F2 (in-frame stop codons after 11, 24, and 35 codons), the early human isolates (H1N1 sequences from 1918 through 1947) have an intact PB1-F2. After 1956, however, a mutation became prevalent such that the recent sequences starting from A/Beijing/1/56 terminate after 57 codons. An exception to this rule is A/Taiwan/3355/97. Two human H1N1 isolates with an intact PB1-F2 coding sequence cluster in the H3N2 clade (A/Kiev/59/79, A/Wisconsin/10/98). The PB1 sequences of European porcine influenza A virus isolates cluster with European porcine H3N2 and H1N2.
Fourth, all H2N2 sequences are monophyletic and encode an intact PB1-F2. Fifth, the main sequence cluster of the H3N2 subtype comprises 3 branches: 1) porcine H3N2 and porcine H1N2 sequences from the United States, 2) porcine H3N2 isolates from Hong Kong and human H1N2, and 3) recent human H3N2 and some Japanese H3N2 isolates. Most of these sequences encode an intact PB1-F2.
Sixth, the cluster of European porcine influenza A virus isolates comprises the subtypes H1N1, H1N2, and H3N2. The lack of distinct clades for each subtype indicates frequent reassortment in the evolution of these viruses. Of the segment-2 sequences, 56% encode an intact PB1-F2.
Seventh, other porcine isolates of various subtypes represent trans-species infections or single reassortment events. And eighth, the segment-2 sequences of many avian influenza A virus isolates encode intact PB1-F2. Considerable proportions of truncated PB1-F2 genes were found in the H5N2, H6N6, H9N2, and H13N2 subtypes. However, because of the small number of sequences available, this observation may not be important.
In conclusion, PB1-F2 is expressed in most avian and many porcine influenza A virus isolates. This finding contrasts with those in the initial publication, which stated that PB1-F2 is not expressed in many animal isolates, particularly those of porcine origin (1). Because PB1-F2 was described as a proapoptotic protein probably counteracting the host immune response, why numerous human and porcine isolates lack this protein without selective disadvantage remains unclear.
Roland Zell, * Andi Krumbholz, * and Peter Wutzler *
* Friedrich Schiller University, Jena, Germany
 
Re: PB1 F2 - properties

Perhaps we can try to summarize all available publications about PB1 F2 in this thread just to give an overview.

Migus has posted a paper about another aspect: Impairment of alveolar macrophage function followed by comprimised defense to bacterial superinfection (BS). Bacterial superinfection is one of the major features of IA infection. It has been hypothesized a "synergy or even symbiose" between IA viruses and bacteria. The pathways are

1. impairment of mucocilial function =>
a) valteres viscosity b) paralysis of ciliar mouvement => mucus is not transported "outside" but stays in the airways ore even moves downstream.

2. impairment of immune response on different levels.
Typical candidates for BS are:
Haemophilus, Streptococci and Staphylokcocci

Some more information about BS here (German)
:::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::
Virology Journal
Commentary Open Access
The PB1-F2 protein of Influenza A virus: increasing pathogenicity by disrupting alveolar macrophages

http://www.flutrackers.com/forum/showthread.php?t=16029&highlight=PB1-F2+protein
 
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