PandemieGrippaleV1, Ncbi, Merge, bibRecord, 001F35

Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza

Identifieur interne : 001F35 ( Ncbi/Merge ); précédent : 001F34; suivant : 001F36

Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza

Auteurs : Eun-Sook Park ; Young Ho Byun ; Soree Park ; Yo Han Jang ; Woo-Ry Han ; Juhee Won ; Kyung Cho Cho ; Doo Hyun Kim ; Ah Ram Lee ; Gu-Choul Shin ; Yong Kwang Park ; Hong Seok Kang ; Heewoo Sim ; Yea Na Ha ; Byeongjune Jae ; Ahyun Son ; Paul Kim ; Jieun Yu ; Hye-Min Lee ; Sun-Bin Kwon ; Kwang Pyo Kim ; Seung-Hyun Lee ; Yeong-Min Park ; Baik L. Seong ; Kyun-Hwan Kim

Source :

The EMBO Journal [ 0261-4189 ] ; 2019.

RBID : PMC:6518015

Descripteurs français

KwdFr :
- Animaux, Cellules A549, Cellules HEK293, Cellules U937, Cellules rénales canines Madin-Darby, Chiens, DEAD-box RNA helicases (métabolisme), Femelle, Grippe humaine (histoire), Grippe humaine (virologie), Grippe humaine (épidémiologie), Histoire du 20ème siècle, Humains, Interférons (métabolisme), Orthomyxoviridae (métabolisme), Orthomyxoviridae (pathogénicité), Pandémies, Protéines virales (métabolisme), Protéines virales (physiologie), Protéolyse, Souris, Souris de lignée BALB C, Transduction du signal, Virulence (physiologie).
MESH :
- histoire : Grippe humaine.
- métabolisme : DEAD-box RNA helicases, Interférons, Orthomyxoviridae, Protéines virales.
- pathogénicité : Orthomyxoviridae.
- physiologie : Protéines virales, Virulence.
- virologie : Grippe humaine.
- épidémiologie : Grippe humaine.
- Animaux, Cellules A549, Cellules HEK293, Cellules U937, Cellules rénales canines Madin-Darby, Chiens, Femelle, Histoire du 20ème siècle, Humains, Pandémies, Protéolyse, Souris, Souris de lignée BALB C, Transduction du signal.

English descriptors

KwdEn :
- A549 Cells, Animals, DEAD-box RNA Helicases (metabolism), Dogs, Female, HEK293 Cells, History, 20th Century, Humans, Influenza, Human (epidemiology), Influenza, Human (history), Influenza, Human (virology), Interferons (metabolism), Madin Darby Canine Kidney Cells, Mice, Mice, Inbred BALB C, Orthomyxoviridae (metabolism), Orthomyxoviridae (pathogenicity), Pandemics, Proteolysis, Signal Transduction, U937 Cells, Viral Proteins (metabolism), Viral Proteins (physiology), Virulence (physiology).
MESH :
- chemical , metabolism : DEAD-box RNA Helicases, Interferons, Viral Proteins.
- epidemiology : Influenza, Human.
- history : Influenza, Human.
- metabolism : Orthomyxoviridae.
- pathogenicity : Orthomyxoviridae.
- chemical , physiology : Viral Proteins, Virulence.
- virology : Influenza, Human.
- A549 Cells, Animals, Dogs, Female, HEK293 Cells, History, 20th Century, Humans, Madin Darby Canine Kidney Cells, Mice, Mice, Inbred BALB C, Pandemics, Proteolysis, Signal Transduction, U937 Cells.

Abstract

The multifunctional influenza virus protein PB1‐F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1‐F2 protein not only interferes with the mitochondria‐dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD‐box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome‐dependent degradation. Interactome analysis revealed that 1918 PB1‐F2, but not PR8 PB1‐F2, binds to DDX3 and causes its co‐degradation. Consistent with intrinsic protein instability as basis for this gain‐of‐function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1‐F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1‐F2‐producing virus. Alongside NS1 protein, 1918 PB1‐F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518015

DOI: 10.15252/embj.201899475
PubMed: 30979777
PubMed Central: 6518015

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PMC:6518015

Le document en format XML

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</affiliation>
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<author><name sortKey="Park, Yong Kwang" sort="Park, Yong Kwang" uniqKey="Park Y" first="Yong Kwang" last="Park">Yong Kwang Park</name>
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<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
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</affiliation>
</author>
<author><name sortKey="Ha, Yea Na" sort="Ha, Yea Na" uniqKey="Ha Y" first="Yea Na" last="Ha">Yea Na Ha</name>
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</affiliation>
</author>
<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
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<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
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</affiliation>
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<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
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</affiliation>
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<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
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</affiliation>
</author>
<author><name sortKey="Lee, Hye In" sort="Lee, Hye In" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
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</affiliation>
</author>
<author><name sortKey="Kwon, Sun In" sort="Kwon, Sun In" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
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</affiliation>
</author>
<author><name sortKey="Kim, Kwang Pyo" sort="Kim, Kwang Pyo" uniqKey="Kim K" first="Kwang Pyo" last="Kim">Kwang Pyo Kim</name>
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<term>Animals</term>
<term>DEAD-box RNA Helicases (metabolism)</term>
<term>Dogs</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>History, 20th Century</term>
<term>Humans</term>
<term>Influenza, Human (epidemiology)</term>
<term>Influenza, Human (history)</term>
<term>Influenza, Human (virology)</term>
<term>Interferons (metabolism)</term>
<term>Madin Darby Canine Kidney Cells</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Orthomyxoviridae (metabolism)</term>
<term>Orthomyxoviridae (pathogenicity)</term>
<term>Pandemics</term>
<term>Proteolysis</term>
<term>Signal Transduction</term>
<term>U937 Cells</term>
<term>Viral Proteins (metabolism)</term>
<term>Viral Proteins (physiology)</term>
<term>Virulence (physiology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Cellules A549</term>
<term>Cellules HEK293</term>
<term>Cellules U937</term>
<term>Cellules rénales canines Madin-Darby</term>
<term>Chiens</term>
<term>DEAD-box RNA helicases (métabolisme)</term>
<term>Femelle</term>
<term>Grippe humaine (histoire)</term>
<term>Grippe humaine (virologie)</term>
<term>Grippe humaine (épidémiologie)</term>
<term>Histoire du 20ème siècle</term>
<term>Humains</term>
<term>Interférons (métabolisme)</term>
<term>Orthomyxoviridae (métabolisme)</term>
<term>Orthomyxoviridae (pathogénicité)</term>
<term>Pandémies</term>
<term>Protéines virales (métabolisme)</term>
<term>Protéines virales (physiologie)</term>
<term>Protéolyse</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Transduction du signal</term>
<term>Virulence (physiologie)</term>
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<term>Virulence</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>A549 Cells</term>
<term>Animals</term>
<term>Dogs</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>History, 20th Century</term>
<term>Humans</term>
<term>Madin Darby Canine Kidney Cells</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Pandemics</term>
<term>Proteolysis</term>
<term>Signal Transduction</term>
<term>U937 Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules A549</term>
<term>Cellules HEK293</term>
<term>Cellules U937</term>
<term>Cellules rénales canines Madin-Darby</term>
<term>Chiens</term>
<term>Femelle</term>
<term>Histoire du 20ème siècle</term>
<term>Humains</term>
<term>Pandémies</term>
<term>Protéolyse</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Transduction du signal</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>The multifunctional influenza virus protein <styled-content style="fixed-case">PB</styled-content>
1‐F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2 protein not only interferes with the mitochondria‐dependent pathway of type I interferon (<styled-content style="fixed-case">IFN</styled-content>
) signaling, but also acquired a novel <styled-content style="fixed-case">IFN</styled-content>
 antagonist function by targeting the <styled-content style="fixed-case">DEAD</styled-content>
‐box helicase <styled-content style="fixed-case">DDX</styled-content>
3, a key downstream mediator in antiviral interferon signaling, toward proteasome‐dependent degradation. Interactome analysis revealed that 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2, but not <styled-content style="fixed-case">PR</styled-content>
8 <styled-content style="fixed-case">PB</styled-content>
1‐F2, binds to <styled-content style="fixed-case">DDX</styled-content>
3 and causes its co‐degradation. Consistent with intrinsic protein instability as basis for this gain‐of‐function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2 protein. Infusing mice with recombinant <styled-content style="fixed-case">DDX</styled-content>
3 protein completely rescued them from lethal infection with the 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2‐producing virus. Alongside <styled-content style="fixed-case">NS</styled-content>
1 protein, 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2 therefore constitutes a potent <styled-content style="fixed-case">IFN</styled-content>
 antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.</p>
</div>
</front>
</TEI>
<double pmid="30979777"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza</title>
<author><name sortKey="Park, Eun Ook" sort="Park, Eun Ook" uniqKey="Park E" first="Eun-Sook" last="Park">Eun-Sook Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0002"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jang, Yo Han" sort="Jang, Yo Han" uniqKey="Jang Y" first="Yo Han" last="Jang">Yo Han Jang</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Han, Woo Y" sort="Han, Woo Y" uniqKey="Han W" first="Woo-Ry" last="Han">Woo-Ry Han</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cho, Kyung Cho" sort="Cho, Kyung Cho" uniqKey="Cho K" first="Kyung Cho" last="Cho">Kyung Cho Cho</name>
<affiliation><nlm:aff id="embj201899475-aff-0005"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Doo Hyun" sort="Kim, Doo Hyun" uniqKey="Kim D" first="Doo Hyun" last="Kim">Doo Hyun Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Ah Ram" sort="Lee, Ah Ram" uniqKey="Lee A" first="Ah Ram" last="Lee">Ah Ram Lee</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shin, Gu Houl" sort="Shin, Gu Houl" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Yong Kwang" sort="Park, Yong Kwang" uniqKey="Park Y" first="Yong Kwang" last="Park">Yong Kwang Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ha, Yea Na" sort="Ha, Yea Na" uniqKey="Ha Y" first="Yea Na" last="Ha">Yea Na Ha</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Hye In" sort="Lee, Hye In" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kwon, Sun In" sort="Kwon, Sun In" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Kwang Pyo" sort="Kim, Kwang Pyo" uniqKey="Kim K" first="Kwang Pyo" last="Kim">Kwang Pyo Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0005"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Seung Yun" sort="Lee, Seung Yun" uniqKey="Lee S" first="Seung-Hyun" last="Lee">Seung-Hyun Lee</name>
<affiliation><nlm:aff id="embj201899475-aff-0006"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Yeong In" sort="Park, Yeong In" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0007"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seong, Baik L" sort="Seong, Baik L" uniqKey="Seong B" first="Baik L" last="Seong">Baik L. Seong</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Kyun Wan" sort="Kim, Kyun Wan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0002"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0008"></nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">30979777</idno>
<idno type="pmc">6518015</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518015</idno>
<idno type="RBID">PMC:6518015</idno>
<idno type="doi">10.15252/embj.201899475</idno>
<date when="2019">2019</date>
<idno type="wicri:Area/Pmc/Corpus">000684</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000684</idno>
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<idno type="wicri:Area/Pmc/Checkpoint">000082</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000082</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza</title>
<author><name sortKey="Park, Eun Ook" sort="Park, Eun Ook" uniqKey="Park E" first="Eun-Sook" last="Park">Eun-Sook Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0002"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jang, Yo Han" sort="Jang, Yo Han" uniqKey="Jang Y" first="Yo Han" last="Jang">Yo Han Jang</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Han, Woo Y" sort="Han, Woo Y" uniqKey="Han W" first="Woo-Ry" last="Han">Woo-Ry Han</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Cho, Kyung Cho" sort="Cho, Kyung Cho" uniqKey="Cho K" first="Kyung Cho" last="Cho">Kyung Cho Cho</name>
<affiliation><nlm:aff id="embj201899475-aff-0005"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Doo Hyun" sort="Kim, Doo Hyun" uniqKey="Kim D" first="Doo Hyun" last="Kim">Doo Hyun Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Ah Ram" sort="Lee, Ah Ram" uniqKey="Lee A" first="Ah Ram" last="Lee">Ah Ram Lee</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Shin, Gu Houl" sort="Shin, Gu Houl" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Yong Kwang" sort="Park, Yong Kwang" uniqKey="Park Y" first="Yong Kwang" last="Park">Yong Kwang Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ha, Yea Na" sort="Ha, Yea Na" uniqKey="Ha Y" first="Yea Na" last="Ha">Yea Na Ha</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Hye In" sort="Lee, Hye In" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kwon, Sun In" sort="Kwon, Sun In" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Kwang Pyo" sort="Kim, Kwang Pyo" uniqKey="Kim K" first="Kwang Pyo" last="Kim">Kwang Pyo Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0005"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Seung Yun" sort="Lee, Seung Yun" uniqKey="Lee S" first="Seung-Hyun" last="Lee">Seung-Hyun Lee</name>
<affiliation><nlm:aff id="embj201899475-aff-0006"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Park, Yeong In" sort="Park, Yeong In" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
<affiliation><nlm:aff id="embj201899475-aff-0007"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Seong, Baik L" sort="Seong, Baik L" uniqKey="Seong B" first="Baik L" last="Seong">Baik L. Seong</name>
<affiliation><nlm:aff id="embj201899475-aff-0003"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kim, Kyun Wan" sort="Kim, Kyun Wan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
<affiliation><nlm:aff id="embj201899475-aff-0001"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0002"></nlm:aff>
</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0008"></nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">The EMBO Journal</title>
<idno type="ISSN">0261-4189</idno>
<idno type="eISSN">1460-2075</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Abstract</title>
<p>The multifunctional influenza virus protein <styled-content style="fixed-case">PB</styled-content>
1‐F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2 protein not only interferes with the mitochondria‐dependent pathway of type I interferon (<styled-content style="fixed-case">IFN</styled-content>
) signaling, but also acquired a novel <styled-content style="fixed-case">IFN</styled-content>
 antagonist function by targeting the <styled-content style="fixed-case">DEAD</styled-content>
‐box helicase <styled-content style="fixed-case">DDX</styled-content>
3, a key downstream mediator in antiviral interferon signaling, toward proteasome‐dependent degradation. Interactome analysis revealed that 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2, but not <styled-content style="fixed-case">PR</styled-content>
8 <styled-content style="fixed-case">PB</styled-content>
1‐F2, binds to <styled-content style="fixed-case">DDX</styled-content>
3 and causes its co‐degradation. Consistent with intrinsic protein instability as basis for this gain‐of‐function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2 protein. Infusing mice with recombinant <styled-content style="fixed-case">DDX</styled-content>
3 protein completely rescued them from lethal infection with the 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2‐producing virus. Alongside <styled-content style="fixed-case">NS</styled-content>
1 protein, 1918 <styled-content style="fixed-case">PB</styled-content>
1‐F2 therefore constitutes a potent <styled-content style="fixed-case">IFN</styled-content>
 antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.</p>
</div>
</front>
</TEI>
</pmc>
<pubmed><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.</title>
<author><name sortKey="Park, Eun Sook" sort="Park, Eun Sook" uniqKey="Park E" first="Eun-Sook" last="Park">Eun-Sook Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jang, Yo Han" sort="Jang, Yo Han" uniqKey="Jang Y" first="Yo Han" last="Jang">Yo Han Jang</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Han, Woo Ry" sort="Han, Woo Ry" uniqKey="Han W" first="Woo-Ry" last="Han">Woo-Ry Han</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
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<author><name sortKey="Cho, Kyung Cho" sort="Cho, Kyung Cho" uniqKey="Cho K" first="Kyung Cho" last="Cho">Kyung Cho Cho</name>
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<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Applied Chemistry, Kyung Hee University, Yongin</wicri:regionArea>
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</author>
<author><name sortKey="Kim, Doo Hyun" sort="Kim, Doo Hyun" uniqKey="Kim D" first="Doo Hyun" last="Kim">Doo Hyun Kim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
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<author><name sortKey="Lee, Ah Ram" sort="Lee, Ah Ram" uniqKey="Lee A" first="Ah Ram" last="Lee">Ah Ram Lee</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
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<region type="capital">Région capitale de Séoul</region>
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<author><name sortKey="Shin, Gu Choul" sort="Shin, Gu Choul" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
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<region type="capital">Région capitale de Séoul</region>
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</author>
<author><name sortKey="Park, Yong Kwang" sort="Park, Yong Kwang" uniqKey="Park Y" first="Yong Kwang" last="Park">Yong Kwang Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
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</author>
<author><name sortKey="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
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<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
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</author>
<author><name sortKey="Ha, Yea Na" sort="Ha, Yea Na" uniqKey="Ha Y" first="Yea Na" last="Ha">Yea Na Ha</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
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<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lee, Hye Min" sort="Lee, Hye Min" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kwon, Sun Bin" sort="Kwon, Sun Bin" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Kwang Pyo" sort="Kim, Kwang Pyo" uniqKey="Kim K" first="Kwang Pyo" last="Kim">Kwang Pyo Kim</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Applied Chemistry, Kyung Hee University, Yongin</wicri:regionArea>
<wicri:noRegion>Yongin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lee, Seung Hyun" sort="Lee, Seung Hyun" uniqKey="Lee S" first="Seung-Hyun" last="Lee">Seung-Hyun Lee</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Microbiology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Microbiology, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Park, Yeong Min" sort="Park, Yeong Min" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
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</placeName>
</affiliation>
</author>
<author><name sortKey="Seong, Baik L" sort="Seong, Baik L" uniqKey="Seong B" first="Baik L" last="Seong">Baik L. Seong</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea blseong@yonsei.ac.kr khkim10@kku.ac.kr.</nlm:affiliation>
<country wicri:rule="url">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Kyun Hwan" sort="Kim, Kyun Hwan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea blseong@yonsei.ac.kr khkim10@kku.ac.kr.</nlm:affiliation>
<country wicri:rule="url">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
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</affiliation>
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</titleStmt>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.</title>
<author><name sortKey="Park, Eun Sook" sort="Park, Eun Sook" uniqKey="Park E" first="Eun-Sook" last="Park">Eun-Sook Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jang, Yo Han" sort="Jang, Yo Han" uniqKey="Jang Y" first="Yo Han" last="Jang">Yo Han Jang</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Han, Woo Ry" sort="Han, Woo Ry" uniqKey="Han W" first="Woo-Ry" last="Han">Woo-Ry Han</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Cho, Kyung Cho" sort="Cho, Kyung Cho" uniqKey="Cho K" first="Kyung Cho" last="Cho">Kyung Cho Cho</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Applied Chemistry, Kyung Hee University, Yongin</wicri:regionArea>
<wicri:noRegion>Yongin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Kim, Doo Hyun" sort="Kim, Doo Hyun" uniqKey="Kim D" first="Doo Hyun" last="Kim">Doo Hyun Kim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lee, Ah Ram" sort="Lee, Ah Ram" uniqKey="Lee A" first="Ah Ram" last="Lee">Ah Ram Lee</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Shin, Gu Choul" sort="Shin, Gu Choul" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Park, Yong Kwang" sort="Park, Yong Kwang" uniqKey="Park Y" first="Yong Kwang" last="Park">Yong Kwang Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Ha, Yea Na" sort="Ha, Yea Na" uniqKey="Ha Y" first="Yea Na" last="Ha">Yea Na Ha</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lee, Hye Min" sort="Lee, Hye Min" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kwon, Sun Bin" sort="Kwon, Sun Bin" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Kwang Pyo" sort="Kim, Kwang Pyo" uniqKey="Kim K" first="Kwang Pyo" last="Kim">Kwang Pyo Kim</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Applied Chemistry, Kyung Hee University, Yongin</wicri:regionArea>
<wicri:noRegion>Yongin</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Lee, Seung Hyun" sort="Lee, Seung Hyun" uniqKey="Lee S" first="Seung-Hyun" last="Lee">Seung-Hyun Lee</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Microbiology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Microbiology, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Park, Yeong Min" sort="Park, Yeong Min" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
<affiliation wicri:level="3"><nlm:affiliation>Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Seong, Baik L" sort="Seong, Baik L" uniqKey="Seong B" first="Baik L" last="Seong">Baik L. Seong</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea blseong@yonsei.ac.kr khkim10@kku.ac.kr.</nlm:affiliation>
<country wicri:rule="url">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kim, Kyun Hwan" sort="Kim, Kyun Hwan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea blseong@yonsei.ac.kr khkim10@kku.ac.kr.</nlm:affiliation>
<country wicri:rule="url">Corée du Sud</country>
<wicri:regionArea>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul</wicri:regionArea>
<placeName><settlement type="city">Séoul</settlement>
<region type="capital">Région capitale de Séoul</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">The EMBO journal</title>
<idno type="eISSN">1460-2075</idno>
<imprint><date when="2019" type="published">2019</date>
</imprint>
</series>
</biblStruct>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>A549 Cells</term>
<term>Animals</term>
<term>DEAD-box RNA Helicases (metabolism)</term>
<term>Dogs</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>History, 20th Century</term>
<term>Humans</term>
<term>Influenza, Human (epidemiology)</term>
<term>Influenza, Human (history)</term>
<term>Influenza, Human (virology)</term>
<term>Interferons (metabolism)</term>
<term>Madin Darby Canine Kidney Cells</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Orthomyxoviridae (metabolism)</term>
<term>Orthomyxoviridae (pathogenicity)</term>
<term>Pandemics</term>
<term>Proteolysis</term>
<term>Signal Transduction</term>
<term>U937 Cells</term>
<term>Viral Proteins (metabolism)</term>
<term>Viral Proteins (physiology)</term>
<term>Virulence (physiology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Cellules A549</term>
<term>Cellules HEK293</term>
<term>Cellules U937</term>
<term>Cellules rénales canines Madin-Darby</term>
<term>Chiens</term>
<term>DEAD-box RNA helicases (métabolisme)</term>
<term>Femelle</term>
<term>Grippe humaine (histoire)</term>
<term>Grippe humaine (virologie)</term>
<term>Grippe humaine (épidémiologie)</term>
<term>Histoire du 20ème siècle</term>
<term>Humains</term>
<term>Interférons (métabolisme)</term>
<term>Orthomyxoviridae (métabolisme)</term>
<term>Orthomyxoviridae (pathogénicité)</term>
<term>Pandémies</term>
<term>Protéines virales (métabolisme)</term>
<term>Protéines virales (physiologie)</term>
<term>Protéolyse</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Transduction du signal</term>
<term>Virulence (physiologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>DEAD-box RNA Helicases</term>
<term>Interferons</term>
<term>Viral Proteins</term>
</keywords>
<keywords scheme="MESH" qualifier="epidemiology" xml:lang="en"><term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" qualifier="histoire" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" qualifier="history" xml:lang="en"><term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Orthomyxoviridae</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>DEAD-box RNA helicases</term>
<term>Interférons</term>
<term>Orthomyxoviridae</term>
<term>Protéines virales</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Orthomyxoviridae</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Orthomyxoviridae</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Protéines virales</term>
<term>Virulence</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Viral Proteins</term>
<term>Virulence</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Influenza, Human</term>
</keywords>
<keywords scheme="MESH" qualifier="épidémiologie" xml:lang="fr"><term>Grippe humaine</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>A549 Cells</term>
<term>Animals</term>
<term>Dogs</term>
<term>Female</term>
<term>HEK293 Cells</term>
<term>History, 20th Century</term>
<term>Humans</term>
<term>Madin Darby Canine Kidney Cells</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Pandemics</term>
<term>Proteolysis</term>
<term>Signal Transduction</term>
<term>U937 Cells</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Cellules A549</term>
<term>Cellules HEK293</term>
<term>Cellules U937</term>
<term>Cellules rénales canines Madin-Darby</term>
<term>Chiens</term>
<term>Femelle</term>
<term>Histoire du 20ème siècle</term>
<term>Humains</term>
<term>Pandémies</term>
<term>Protéolyse</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Transduction du signal</term>
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<front><div type="abstract" xml:lang="en">The multifunctional influenza virus protein PB1-F2 plays several roles in deregulation of host innate immune responses and is a known immunopathology enhancer of the 1918 influenza pandemic. Here, we show that the 1918 PB1-F2 protein not only interferes with the mitochondria-dependent pathway of type I interferon (IFN) signaling, but also acquired a novel IFN antagonist function by targeting the DEAD-box helicase DDX3, a key downstream mediator in antiviral interferon signaling, toward proteasome-dependent degradation. Interactome analysis revealed that 1918 PB1-F2, but not PR8 PB1-F2, binds to DDX3 and causes its co-degradation. Consistent with intrinsic protein instability as basis for this gain-of-function, internal structural disorder is associated with the unique cytotoxic sequences of the 1918 PB1-F2 protein. Infusing mice with recombinant DDX3 protein completely rescued them from lethal infection with the 1918 PB1-F2-producing virus. Alongside NS1 protein, 1918 PB1-F2 therefore constitutes a potent IFN antagonist causative for the severe pathogenicity of the 1918 influenza strain. Our identification of molecular determinants of pathogenesis should be useful for the future design of new antiviral strategies against influenza pandemics.</div>
</front>
</TEI>
</pubmed>
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Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza

Co‐degradation of interferon signaling factor DDX3 by PB1‐F2 as a basis for high virulence of 1918 pandemic influenza

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