PandemieGrippaleV1, PubMed, Curation, bibRecord, 000159

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

Identifieur interne : 000159 ( PubMed/Curation ); précédent : 000158; suivant : 000160

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

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

Source :

The EMBO journal [ 1460-2075 ] ; 2019.

RBID : pubmed:30979777

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.

DOI: 10.15252/embj.201899475
PubMed: 30979777

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<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
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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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<author><name sortKey="Shin, Gu Choul" sort="Shin, Gu Choul" uniqKey="Shin G" first="Gu-Choul" last="Shin">Gu-Choul Shin</name>
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<country xml:lang="fr">Corée du Sud</country>
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<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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<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
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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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<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
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<author><name sortKey="Lee, Hye Min" sort="Lee, Hye Min" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
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<author><name sortKey="Kwon, Sun Bin" sort="Kwon, Sun Bin" uniqKey="Kwon S" first="Sun-Bin" last="Kwon">Sun-Bin Kwon</name>
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<country xml:lang="fr">Corée du Sud</country>
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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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<country xml:lang="fr">Corée du Sud</country>
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<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="1"><nlm:affiliation>Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
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<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="1"><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>
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<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="1"><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>
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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="1"><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>
</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="1"><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>
</affiliation>
</author>
<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<affiliation wicri:level="1"><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>
</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="1"><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>
</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="1"><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>
</affiliation>
</author>
<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<affiliation wicri:level="1"><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>
</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>
</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="1"><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>
</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="1"><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>
</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="1"><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>
</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="1"><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>
</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="1"><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>
</affiliation>
</author>
<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<affiliation wicri:level="1"><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>
</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="1"><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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<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="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
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<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
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<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
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<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lee, Hye Min" sort="Lee, Hye Min" uniqKey="Lee H" first="Hye-Min" last="Lee">Hye-Min Lee</name>
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<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul</wicri:regionArea>
</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="1"><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>
</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>
</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="1"><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>
</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="1"><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>
</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="1"><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>
</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="1"><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>
</affiliation>
</author>
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<series><title level="j">The EMBO journal</title>
<idno type="eISSN">1460-2075</idno>
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<term>Female</term>
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<term>History, 20th Century</term>
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<term>Influenza, Human (epidemiology)</term>
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<term>Influenza, Human (virology)</term>
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<term>Madin Darby Canine Kidney Cells</term>
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<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>
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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><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30979777</PMID>
<DateCompleted><Year>2020</Year>
<Month>01</Month>
<Day>06</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>05</Month>
<Day>16</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2075</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>38</Volume>
<Issue>10</Issue>
<PubDate><Year>2019</Year>
<Month>05</Month>
<Day>15</Day>
</PubDate>
</JournalIssue>
<Title>The EMBO journal</Title>
<ISOAbbreviation>EMBO J.</ISOAbbreviation>
</Journal>
<ArticleTitle>Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.</ArticleTitle>
<ELocationID EIdType="pii" ValidYN="Y">e99475</ELocationID>
<ELocationID EIdType="doi" ValidYN="Y">10.15252/embj.201899475</ELocationID>
<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>© 2019 The Authors.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Park</LastName>
<ForeName>Eun-Sook</ForeName>
<Initials>ES</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>KU Open Innovation Center, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Byun</LastName>
<ForeName>Young Ho</ForeName>
<Initials>YH</Initials>
<Identifier Source="ORCID">0000-0001-9306-9485</Identifier>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Vaccine Translational Research Center, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Park</LastName>
<ForeName>Soree</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jang</LastName>
<ForeName>Yo Han</ForeName>
<Initials>YH</Initials>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Vaccine Translational Research Center, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Han</LastName>
<ForeName>Woo-Ry</ForeName>
<Initials>WR</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Won</LastName>
<ForeName>Juhee</ForeName>
<Initials>J</Initials>
<Identifier Source="ORCID">0000-0002-5757-3745</Identifier>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cho</LastName>
<ForeName>Kyung Cho</ForeName>
<Initials>KC</Initials>
<Identifier Source="ORCID">0000-0003-0483-9543</Identifier>
<AffiliationInfo><Affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Doo Hyun</ForeName>
<Initials>DH</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Ah Ram</ForeName>
<Initials>AR</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Shin</LastName>
<ForeName>Gu-Choul</ForeName>
<Initials>GC</Initials>
<Identifier Source="ORCID">0000-0001-8200-9700</Identifier>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Park</LastName>
<ForeName>Yong Kwang</ForeName>
<Initials>YK</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kang</LastName>
<ForeName>Hong Seok</ForeName>
<Initials>HS</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sim</LastName>
<ForeName>Heewoo</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ha</LastName>
<ForeName>Yea Na</ForeName>
<Initials>YN</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jae</LastName>
<ForeName>Byeongjune</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Son</LastName>
<ForeName>Ahyun</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Paul</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Vaccine Translational Research Center, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yu</LastName>
<ForeName>Jieun</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Hye-Min</ForeName>
<Initials>HM</Initials>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kwon</LastName>
<ForeName>Sun-Bin</ForeName>
<Initials>SB</Initials>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Kwang Pyo</ForeName>
<Initials>KP</Initials>
<AffiliationInfo><Affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Seung-Hyun</ForeName>
<Initials>SH</Initials>
<AffiliationInfo><Affiliation>Department of Microbiology, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Park</LastName>
<ForeName>Yeong-Min</ForeName>
<Initials>YM</Initials>
<AffiliationInfo><Affiliation>Laboratory of Dendritic Cell Differentiation and Regulation, Department of Immunology, School of Medicine, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Seong</LastName>
<ForeName>Baik L</ForeName>
<Initials>BL</Initials>
<Identifier Source="ORCID">0000-0002-7301-082X</Identifier>
<AffiliationInfo><Affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea blseong@yonsei.ac.kr khkim10@kku.ac.kr.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Vaccine Translational Research Center, Yonsei University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kim</LastName>
<ForeName>Kyun-Hwan</ForeName>
<Initials>KH</Initials>
<Identifier Source="ORCID">0000-0001-5266-072X</Identifier>
<AffiliationInfo><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.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>KU Open Innovation Center, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Research Institute of Medical Science, Konkuk University, Seoul, Korea.</Affiliation>
</AffiliationInfo>
</Author>
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<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016456">Historical Article</PublicationType>
<PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
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<ArticleDate DateType="Electronic"><Year>2019</Year>
<Month>04</Month>
<Day>12</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>England</Country>
<MedlineTA>EMBO J</MedlineTA>
<NlmUniqueID>8208664</NlmUniqueID>
<ISSNLinking>0261-4189</ISSNLinking>
</MedlineJournalInfo>
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</Chemical>
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<Chemical><RegistryNumber>9008-11-1</RegistryNumber>
<NameOfSubstance UI="D007372">Interferons</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.6.1.-</RegistryNumber>
<NameOfSubstance UI="C119332">DDX3X protein, human</NameOfSubstance>
</Chemical>
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<NameOfSubstance UI="D053487">DEAD-box RNA Helicases</NameOfSubstance>
</Chemical>
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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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