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Article ; Online: SARS-CoV-2 variant-specific differences in inhibiting the effects of the PKR-activated integrated stress response.

Christ, Wanda / Klingström, Jonas / Tynell, Janne

2023 Volume 339, Page(s) 199271

Abstract: The integrated stress response (ISR) is a eukaryotic cell pathway that triggers translational arrest and the formation of stress granules (SGs) in response to various stress signals, including those caused by viral infections. The SARS-CoV-2 nucleocapsid ...

Abstract	The integrated stress response (ISR) is a eukaryotic cell pathway that triggers translational arrest and the formation of stress granules (SGs) in response to various stress signals, including those caused by viral infections. The SARS-CoV-2 nucleocapsid protein has been shown to disrupt SGs, but SARS-CoV-2 interactions with other components of the pathway remains poorly characterized. Here, we show that SARS-CoV-2 infection triggers the ISR through activation of the eIF2α-kinase PKR while inhibiting a variety of downstream effects. In line with previous studies, SG formation was efficiently inhibited and the induced eIF2α phosphorylation only minimally contributed to the translational arrest observed in infected cells. Despite ISR activation and translational arrest, expression of the stress-responsive transcription factors ATF4 and CHOP was not induced in SARS-CoV-2 infected cells. Finally, we found variant-specific differences in the activation of the ISR between ancestral SARS-CoV-2 and the Delta and Omicron BA.1 variants in that Delta infection induced weaker PKR activation while Omicron infection induced higher levels of p-eIF2α, and greatly increased SG formation compared to the other variants. Our results suggest that different SARS-CoV-2 variants can affect normal cell functions differently, which can have an impact on pathogenesis and treatment strategies.
MeSH term(s)	Humans ; COVID-19/virology ; Phosphorylation ; SARS-CoV-2 ; Stress, Physiological ; eIF-2 Kinase/metabolism
Chemical Substances	EIF2AK2 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2023-11-28
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2023.199271
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Article ; Online: SARS-CoV-2 variant-specific differences in inhibiting the effects of the PKR-activated integrated stress response

Christ, Wanda / Klingstrom, Jonas / Tynell, Janne

bioRxiv

Abstract	The integrated stress response (ISR) is a eukaryotic cell pathway that triggers translational arrest and the formation of stress granules (SGs) in response to various stress signals, including those caused by viral infections. The SARS-CoV-2 nucleocapsid protein has been shown to disrupt SGs, but SARS-CoV-2 interactions with other components of the pathway remains poorly characterized. Here, we show that SARS-CoV-2 infection triggers the ISR through activation of the eIF2α-kinase PKR while inhibiting a variety of downstream effects. In line with previous studies, SG formation was efficiently inhibited and the induced eIF2α phosphorylation only minimally contributed to the translational arrest observed in infected cells. Despite ISR activation and translational arrest, expression of the stress-responsive transcripts ATF4 and CHOP was not induced in SARS-CoV-2 infected cells. Finally, we found variant-specific differences in the activation of the ISR between ancestral SARS-CoV-2 and the Delta and Omicron BA.1 variants in that Delta infection induced weaker PKR activation while Omicron infection induced higher levels of p-eIF2α and greatly increased SG formation compared to the other variants. Our results suggest that different SARS-CoV-2 variants can affect normal cell functions differently, which can have an impact on pathogenesis and treatment strategies.
Keywords	covid19
Language	English
Publishing date	2022-12-21
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.12.21.521388
Database	COVID19

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Article ; Online: Puumala and Andes Orthohantaviruses Cause Transient Protein Kinase R-Dependent Formation of Stress Granules.

Christ, Wanda / Tynell, Janne / Klingström, Jonas

Journal of virology

2020 Volume 94, Issue 3

Abstract: Virus infection frequently triggers host cell stress signaling resulting in translational arrest; as a consequence, many viruses employ means to modulate the host stress response. Hantaviruses are negative-sense, single-stranded RNA viruses known to ... ...

Abstract	Virus infection frequently triggers host cell stress signaling resulting in translational arrest; as a consequence, many viruses employ means to modulate the host stress response. Hantaviruses are negative-sense, single-stranded RNA viruses known to inhibit host innate immune responses and apoptosis, but their impact on host cell stress signaling remains largely unknown. In this study, we investigated activation of host cell stress responses during hantavirus infection. We show that hantavirus infection causes transient formation of stress granules (SGs) but does so in only a limited proportion of infected cells. Our data indicate some cell type-specific and hantavirus species-specific variability in SG prevalence and show SG formation to be dependent on the activation of protein kinase R (PKR). Hantavirus infection inhibited PKR-dependent SG formation, which could account for the transient nature and low prevalence of SG formation observed during hantavirus infection. In addition, we report only limited colocalization of hantaviral proteins or RNA with SGs and show evidence indicating hantavirus-mediated inhibition of PKR-like endoplasmic reticulum (ER) kinase (PERK).
MeSH term(s)	Cell Line ; Hantavirus/physiology ; Hantavirus Infections/virology ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Immunity, Innate ; Orthohepadnavirus/physiology ; Puumala virus/physiology ; Signal Transduction ; Viral Proteins/metabolism ; eIF-2 Kinase/metabolism
Chemical Substances	Viral Proteins ; EIF2AK2 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2020-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01168-19
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Article ; Online: Comprehensive proteomics and meta-analysis of COVID-19 host response.

Babačić, Haris / Christ, Wanda / Araújo, José Eduardo / Mermelekas, Georgios / Sharma, Nidhi / Tynell, Janne / García, Marina / Varnaite, Renata / Asgeirsson, Hilmir / Glans, Hedvig / Lehtiö, Janne / Gredmark-Russ, Sara / Klingström, Jonas / Pernemalm, Maria

Nature communications

2023 Volume 14, Issue 1, Page(s) 5921

Abstract: COVID-19 is characterised by systemic immunological perturbations in the human body, which can lead to multi-organ damage. Many of these processes are considered to be mediated by the blood. Therefore, to better understand the systemic host response to ... ...

Abstract	COVID-19 is characterised by systemic immunological perturbations in the human body, which can lead to multi-organ damage. Many of these processes are considered to be mediated by the blood. Therefore, to better understand the systemic host response to SARS-CoV-2 infection, we performed systematic analyses of the circulating, soluble proteins in the blood through global proteomics by mass-spectrometry (MS) proteomics. Here, we show that a large part of the soluble blood proteome is altered in COVID-19, among them elevated levels of interferon-induced and proteasomal proteins. Some proteins that have alternating levels in human cells after a SARS-CoV-2 infection in vitro and in different organs of COVID-19 patients are deregulated in the blood, suggesting shared infection-related changes.The availability of different public proteomic resources on soluble blood proteome alterations leaves uncertainty about the change of a given protein during COVID-19. Hence, we performed a systematic review and meta-analysis of MS global proteomics studies of soluble blood proteomes, including up to 1706 individuals (1039 COVID-19 patients), to provide concluding estimates for the alteration of 1517 soluble blood proteins in COVID-19. Finally, based on the meta-analysis we developed CoViMAPP, an open-access resource for effect sizes of alterations and diagnostic potential of soluble blood proteins in COVID-19, which is publicly available for the research, clinical, and academic community.
MeSH term(s)	Humans ; COVID-19 ; Proteome ; Proteomics ; SARS-CoV-2 ; Cytoplasm
Chemical Substances	Proteome
Language	English
Publishing date	2023-09-22
Publishing country	England
Document type	Meta-Analysis ; Systematic Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41159-z
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Article ; Online: Mutations within the conserved NS1 nuclear export signal lead to inhibition of influenza A virus replication.

Tynell, Janne / Melén, Krister / Julkunen, Ilkka

Virology journal

2014 Volume 11, Page(s) 128

Abstract: Background: The influenza A virus NS1 protein is a virulence factor and an antagonist of host cell innate immune responses. During virus infection NS1 protein has several functions both in the nucleus and in the cytoplasm and its intracellular ... ...

Abstract	Background: The influenza A virus NS1 protein is a virulence factor and an antagonist of host cell innate immune responses. During virus infection NS1 protein has several functions both in the nucleus and in the cytoplasm and its intracellular localization is regulated by one or two nuclear localization signals (NLS) and a nuclear export signal (NES). Methods: In order to investigate the role of NS1 NES in intracellular localization, virus life cycle and host interferon responses, we generated recombinant A/Udorn/72 viruses harboring point mutations in the NES sequence. Results: NS1 NES was found to be inactivated by several of the mutations resulting in nuclear retention of NS1 at late stages of infection confirming that this sequence is a bona fide functional NES. Some of the mutant viruses showed reduced growth properties in cell culture, inability to antagonize host cell interferon production and increased p-IRF3 levels, but no clear correlation between these phenotypes and NS1 localization could be made. Impaired activation of Akt phosphorylation by the replication-deficient viruses indicates possible disruption of NS1-p85β interaction by mutations in the NES region. Conclusion: We conclude that mutations within the NS1 NES result in impairment of several NS1 functions which extends further from the NES site being only involved in regulating the nuclear-cytoplasmic trafficking of NS1.
MeSH term(s)	Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Cleavage And Polyadenylation Specificity Factor/metabolism ; Conserved Sequence ; Cytoplasm/metabolism ; Humans ; Influenza A virus/genetics ; Influenza, Human/virology ; Interferon-gamma/biosynthesis ; Karyopherins/metabolism ; Models, Molecular ; Mutation ; Nuclear Export Signals/genetics ; Protein Binding ; Protein Conformation ; Protein Transport ; Receptors, Cytoplasmic and Nuclear/metabolism ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Virus Replication/genetics ; Exportin 1 Protein
Chemical Substances	Cleavage And Polyadenylation Specificity Factor ; INS1 protein, influenza virus ; Karyopherins ; Nuclear Export Signals ; Receptors, Cytoplasmic and Nuclear ; Viral Nonstructural Proteins ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2014-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2160640-7
ISSN	1743-422X ; 1743-422X
ISSN (online)	1743-422X
ISSN	1743-422X
DOI	10.1186/1743-422X-11-128
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody.

Mittler, Eva / Serris, Alexandra / Esterman, Emma S / Florez, Catalina / Polanco, Laura C / O'Brien, Cecilia M / Slough, Megan M / Tynell, Janne / Gröning, Remigius / Sun, Yan / Abelson, Dafna M / Wec, Anna Z / Haslwanter, Denise / Keller, Markus / Ye, Chunyan / Bakken, Russel R / Jangra, Rohit K / Dye, John M / Ahlm, Clas /

Rappazzo, C Garrett / Ulrich, Rainer G / Zeitlin, Larry / Geoghegan, James C / Bradfute, Steven B / Sidoli, Simone / Forsell, Mattias N E / Strandin, Tomas / Rey, Felix A / Herbert, Andrew S / Walker, Laura M / Chandran, Kartik / Guardado-Calvo, Pablo

Science translational medicine

2023 Volume 15, Issue 700, Page(s) eadg1855

Abstract: Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its ... ...

Abstract	Emerging rodent-borne hantaviruses cause severe diseases in humans with no approved vaccines or therapeutics. We recently isolated a monoclonal broadly neutralizing antibody (nAb) from a Puumala virus-experienced human donor. Here, we report its structure bound to its target, the Gn/Gc glycoprotein heterodimer comprising the viral fusion complex. The structure explains the broad activity of the nAb: It recognizes conserved Gc fusion loop sequences and the main chain of variable Gn sequences, thereby straddling the Gn/Gc heterodimer and locking it in its prefusion conformation. We show that the nAb's accelerated dissociation from the divergent Andes virus Gn/Gc at endosomal acidic pH limits its potency against this highly lethal virus and correct this liability by engineering an optimized variant that sets a benchmark as a candidate pan-hantavirus therapeutic.
MeSH term(s)	Humans ; Antibodies, Viral ; Benchmarking ; Broadly Neutralizing Antibodies ; Conserved Sequence ; Orthohantavirus
Chemical Substances	Antibodies, Viral ; Broadly Neutralizing Antibodies
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adg1855
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Article ; Online: Influenza A H3N2 subtype virus NS1 protein targets into the nucleus and binds primarily via its C-terminal NLS2/NoLS to nucleolin and fibrillarin

Melén Krister / Tynell Janne / Fagerlund Riku / Roussel Pascal / Hernandez-Verdun Danièle / Julkunen Ilkka

Virology Journal, Vol 9, Iss 1, p

2012 Volume 167

Abstract: Abstract Background Influenza A virus non-structural protein 1 (NS1) is a virulence factor, which is targeted into the cell cytoplasm, nucleus and nucleolus. NS1 is a multi-functional protein that inhibits host cell pre-mRNA processing and counteracts ... ...

Abstract	Abstract Background Influenza A virus non-structural protein 1 (NS1) is a virulence factor, which is targeted into the cell cytoplasm, nucleus and nucleolus. NS1 is a multi-functional protein that inhibits host cell pre-mRNA processing and counteracts host cell antiviral responses. Previously, we have shown that the NS1 protein of the H3N2 subtype influenza viruses possesses a C-terminal nuclear localization signal (NLS) that also functions as a nucleolar localization signal (NoLS) and targets the protein into the nucleolus. Results Here, we show that the NS1 protein of the human H3N2 virus subtype interacts in vitro primarily via its C-terminal NLS2/NoLS and to a minor extent via its N-terminal NLS1 with the nucleolar proteins, nucleolin and fibrillarin. Using chimeric green fluorescence protein (GFP)-NS1 fusion constructs, we show that the nucleolar retention of the NS1 protein is determined by its C-terminal NLS2/NoLS in vivo . Confocal laser microscopy analysis shows that the NS1 protein colocalizes with nucleolin in nucleoplasm and nucleolus and with B23 and fibrillarin in the nucleolus of influenza A/Udorn/72 virus-infected A549 cells. Since some viral proteins contain NoLSs, it is likely that viruses have evolved specific nucleolar functions. Conclusion NS1 protein of the human H3N2 virus interacts primarily via the C-terminal NLS2/NoLS and to a minor extent via the N-terminal NLS1 with the main nucleolar proteins, nucleolin, B23 and fibrillarin.
Keywords	Influenza A virus ; NS1 protein ; NoLS ; Nucleolus ; Nucleolin ; B23 ; Fibrillarin ; Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Medicine (General) ; R5-920 ; Medicine ; R ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	570
Language	English
Publishing date	2012-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Novel avian influenza A (H7N9) virus induces impaired interferon responses in human dendritic cells.

Arilahti, Veera / Mäkelä, Sanna M / Tynell, Janne / Julkunen, Ilkka / Österlund, Pamela

PloS one

2014 Volume 9, Issue 5, Page(s) e96350

Abstract: In March 2013 a new avian influenza A(H7N9) virus emerged in China and infected humans with a case fatality rate of over 30%. Like the highly pathogenic H5N1 virus, H7N9 virus is causing severe respiratory distress syndrome in most patients. Based on ... ...

Abstract	In March 2013 a new avian influenza A(H7N9) virus emerged in China and infected humans with a case fatality rate of over 30%. Like the highly pathogenic H5N1 virus, H7N9 virus is causing severe respiratory distress syndrome in most patients. Based on genetic analysis this avian influenza A virus shows to some extent adaptation to mammalian host. In the present study, we analyzed the activation of innate immune responses by this novel H7N9 influenza A virus and compared these responses to those induced by the avian H5N1 and seasonal H3N2 viruses in human monocyte-derived dendritic cells (moDCs). We observed that in H7N9 virus-infected cells, interferon (IFN) responses were weak although the virus replicated as well as the H5N1 and H3N2 viruses in moDCs. H7N9 virus-induced expression of pro-inflammatory cytokines remained at a significantly lower level as compared to H5N1 virus-induced "cytokine storm" seen in human moDCs. However, the H7N9 virus was extremely sensitive to the antiviral effects of IFN-α and IFN-β in pretreated cells. Our data indicates that different highly pathogenic avian viruses may show considerable differences in their ability to induce host antiviral responses in human primary cell models such as moDCs. The unexpected appearance of the novel H7N9 virus clearly emphasizes the importance of the global influenza surveillance system. It is, however, equally important to systematically characterize in normal human cells the replication capacity of the new viruses and their ability to induce and respond to natural antiviral substances such as IFNs.
MeSH term(s)	Cytokines/biosynthesis ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/virology ; Humans ; Influenza A Virus, H7N9 Subtype ; Interferon-alpha/pharmacology ; Interferon-beta/pharmacology ; Virus Replication/drug effects
Chemical Substances	Cytokines ; Interferon-alpha ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2014-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0096350
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Expansion of SARS-CoV-2-Specific Antibody-Secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients.

Varnaitė, Renata / García, Marina / Glans, Hedvig / Maleki, Kimia T / Sandberg, John Tyler / Tynell, Janne / Christ, Wanda / Lagerqvist, Nina / Asgeirsson, Hilmir / Ljunggren, Hans-Gustaf / Ahlén, Gustaf / Frelin, Lars / Sällberg, Matti / Blom, Kim / Klingström, Jonas / Gredmark-Russ, Sara

Journal of immunology (Baltimore, Md. : 1950)

2020 Volume 205, Issue 9, Page(s) 2437–2446

Abstract: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific Abs are typically a major predictor of protective immunity, yet ... ...

Abstract	Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific Abs are typically a major predictor of protective immunity, yet human B cell and Ab responses during COVID-19 are not fully understood. In this study, we analyzed Ab-secreting cell and Ab responses in 20 hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19 and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific Ab-secreting cells in all 20 COVID-19 patients using a multicolor FluoroSpot Assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing Abs by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG, and IgM Ab levels positively correlated with SARS-CoV-2-neutralizing Ab titers, suggesting that SARS-CoV-2-specific Ab levels may reflect the titers of neutralizing Abs in COVID-19 patients during the acute phase of infection. Last, we showed that IL-6 and C-reactive protein serum concentrations were higher in patients who were hospitalized for longer, supporting the recent observations that IL-6 and C-reactive protein could be used as markers for COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in 20 COVID-19 patients, with a focus on B cell and Ab responses, and describes tools to study immune responses to SARS-CoV-2 infection and vaccination.
MeSH term(s)	Adult ; Aged ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; B-Lymphocytes/immunology ; Betacoronavirus/immunology ; Biomarkers/blood ; C-Reactive Protein/analysis ; COVID-19 ; Cohort Studies ; Coronavirus Infections/epidemiology ; Coronavirus Infections/immunology ; Coronavirus Infections/virology ; Coronavirus Nucleocapsid Proteins ; Female ; Hospitalization ; Humans ; Immunoglobulin A/blood ; Immunoglobulin G/blood ; Immunoglobulin M/blood ; Interleukin-6/blood ; Lymphocyte Activation ; Male ; Middle Aged ; Nucleocapsid Proteins/immunology ; Pandemics ; Phosphoproteins ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/immunology ; Pneumonia, Viral/virology ; SARS-CoV-2 ; Sweden/epidemiology
Chemical Substances	Antibodies, Neutralizing ; Antibodies, Viral ; Biomarkers ; Coronavirus Nucleocapsid Proteins ; IL6 protein, human ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Interleukin-6 ; Nucleocapsid Proteins ; Phosphoproteins ; nucleocapsid phosphoprotein, SARS-CoV-2 ; C-Reactive Protein (9007-41-4)
Keywords	covid19
Language	English
Publishing date	2020-09-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2000717
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Article: Influenza A H3N2 subtype virus NS1 protein targets into the nucleus and binds primarily via its C-terminal NLS2/NoLS to nucleolin and fibrillarin

Melén, Krister / Tynell, Janne / Fagerlund, Riku / Roussel, Pascal / Hernandez-Verdun, Danièle / Julkunen, Ilkka

Virology journal. 2012 Dec., v. 9, no. 1

2012

Abstract: BACKGROUND: Influenza A virus non-structural protein 1 (NS1) is a virulence factor, which is targeted into the cell cytoplasm, nucleus and nucleolus. NS1 is a multi-functional protein that inhibits host cell pre-mRNA processing and counteracts host cell ... ...

Abstract	BACKGROUND: Influenza A virus non-structural protein 1 (NS1) is a virulence factor, which is targeted into the cell cytoplasm, nucleus and nucleolus. NS1 is a multi-functional protein that inhibits host cell pre-mRNA processing and counteracts host cell antiviral responses. Previously, we have shown that the NS1 protein of the H3N2 subtype influenza viruses possesses a C-terminal nuclear localization signal (NLS) that also functions as a nucleolar localization signal (NoLS) and targets the protein into the nucleolus. RESULTS: Here, we show that the NS1 protein of the human H3N2 virus subtype interacts in vitro primarily via its C-terminal NLS2/NoLS and to a minor extent via its N-terminal NLS1 with the nucleolar proteins, nucleolin and fibrillarin. Using chimeric green fluorescence protein (GFP)-NS1 fusion constructs, we show that the nucleolar retention of the NS1 protein is determined by its C-terminal NLS2/NoLS in vivo. Confocal laser microscopy analysis shows that the NS1 protein colocalizes with nucleolin in nucleoplasm and nucleolus and with B23 and fibrillarin in the nucleolus of influenza A/Udorn/72 virus-infected A549 cells. Since some viral proteins contain NoLSs, it is likely that viruses have evolved specific nucleolar functions. CONCLUSION: NS1 protein of the human H3N2 virus interacts primarily via the C-terminal NLS2/NoLS and to a minor extent via the N-terminal NLS1 with the main nucleolar proteins, nucleolin, B23 and fibrillarin.
Keywords	Influenza A virus ; cell nucleolus ; confocal laser scanning microscopy ; cytoplasm ; green fluorescent protein ; influenza ; nuclear localization signals ; viral nonstructural proteins ; virulence ; viruses
Language	English
Dates of publication	2012-12
Size	p. 167.
Publishing place	BioMed Central
Document type	Article
ISSN	1743-422X
DOI	10.1186/1743-422X-9-167
Database	NAL-Catalogue (AGRICOLA)

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