PandemieGrippaleV1, Main, Exploration, bibRecord, 000357

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

Identifieur interne : 000357 ( Main/Exploration ); précédent : 000356; suivant : 000358

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

Affiliations:

Le document en format XML

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<author><name sortKey="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
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<author><name sortKey="Kim, Kyun Wan" sort="Kim, Kyun Wan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
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<author><name sortKey="Shin, Gu Houl" sort="Shin, Gu Houl" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
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</affiliation>
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</affiliation>
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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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</affiliation>
</author>
<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
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</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
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</affiliation>
<affiliation><nlm:aff id="embj201899475-aff-0004"></nlm:aff>
</affiliation>
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<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>
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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>Protéines virales</term>
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<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>
</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>
<affiliations><list></list>
<tree><noCountry><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<name sortKey="Cho, Kyung Cho" sort="Cho, Kyung Cho" uniqKey="Cho K" first="Kyung Cho" last="Cho">Kyung Cho Cho</name>
<name sortKey="Ha, Yea Na" sort="Ha, Yea Na" uniqKey="Ha Y" first="Yea Na" last="Ha">Yea Na Ha</name>
<name sortKey="Han, Woo Y" sort="Han, Woo Y" uniqKey="Han W" first="Woo-Ry" last="Han">Woo-Ry Han</name>
<name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<name sortKey="Jang, Yo Han" sort="Jang, Yo Han" uniqKey="Jang Y" first="Yo Han" last="Jang">Yo Han Jang</name>
<name sortKey="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
<name sortKey="Kim, Doo Hyun" sort="Kim, Doo Hyun" uniqKey="Kim D" first="Doo Hyun" last="Kim">Doo Hyun Kim</name>
<name sortKey="Kim, Kwang Pyo" sort="Kim, Kwang Pyo" uniqKey="Kim K" first="Kwang Pyo" last="Kim">Kwang Pyo Kim</name>
<name sortKey="Kim, Kyun Wan" sort="Kim, Kyun Wan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
<name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
<name sortKey="Kwon, Sun In" sort="Kwon, Sun In" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
<name sortKey="Lee, Ah Ram" sort="Lee, Ah Ram" uniqKey="Lee A" first="Ah Ram" last="Lee">Ah Ram Lee</name>
<name sortKey="Lee, Hye In" sort="Lee, Hye In" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
<name sortKey="Lee, Seung Yun" sort="Lee, Seung Yun" uniqKey="Lee S" first="Seung-Hyun" last="Lee">Seung-Hyun Lee</name>
<name sortKey="Park, Eun Ook" sort="Park, Eun Ook" uniqKey="Park E" first="Eun-Sook" last="Park">Eun-Sook Park</name>
<name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<name sortKey="Park, Yeong In" sort="Park, Yeong In" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
<name sortKey="Park, Yong Kwang" sort="Park, Yong Kwang" uniqKey="Park Y" first="Yong Kwang" last="Park">Yong Kwang Park</name>
<name sortKey="Seong, Baik L" sort="Seong, Baik L" uniqKey="Seong B" first="Baik L" last="Seong">Baik L. Seong</name>
<name sortKey="Shin, Gu Houl" sort="Shin, Gu Houl" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
<name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
<name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
</noCountry>
</tree>
</affiliations>
</record>

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Serveur d'exploration sur les pandémies grippales

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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