Co-degradation of interferon signaling factor DDX3 by PB1-F2 as a basis for high virulence of 1918 pandemic influenza.
Identifieur interne : 000159 ( PubMed/Corpus ); précédent : 000158; suivant : 000160Co-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 KimSource :
- The EMBO journal [ 1460-2075 ] ; 2019.
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
Links to Exploration step
pubmed:30979777Le document en format XML
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<author><name sortKey="Park, Eun Sook" sort="Park, Eun Sook" uniqKey="Park E" first="Eun-Sook" last="Park">Eun-Sook Park</name>
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<author><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<affiliation><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
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<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
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<author><name sortKey="Jang, Yo Han" sort="Jang, Yo Han" uniqKey="Jang Y" first="Yo Han" last="Jang">Yo Han Jang</name>
<affiliation><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Han, Woo Ry" sort="Han, Woo Ry" uniqKey="Han W" first="Woo-Ry" last="Han">Woo-Ry Han</name>
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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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</affiliation>
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<author><name sortKey="Kim, Doo Hyun" sort="Kim, Doo Hyun" uniqKey="Kim D" first="Doo Hyun" last="Kim">Doo Hyun Kim</name>
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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>
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</affiliation>
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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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<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="Kang, Hong Seok" sort="Kang, Hong Seok" uniqKey="Kang H" first="Hong Seok" last="Kang">Hong Seok Kang</name>
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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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<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>
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<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<affiliation><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</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>
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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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</affiliation>
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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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</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:affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</nlm:affiliation>
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<author><name sortKey="Lee, Seung Hyun" sort="Lee, Seung Hyun" uniqKey="Lee S" first="Seung-Hyun" last="Lee">Seung-Hyun Lee</name>
<affiliation><nlm:affiliation>Department of Microbiology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Park, Yeong Min" sort="Park, Yeong Min" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
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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><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>
</affiliation>
</author>
<author><name sortKey="Kim, Kyun Hwan" sort="Kim, Kyun Hwan" uniqKey="Kim K" first="Kyun-Hwan" last="Kim">Kyun-Hwan Kim</name>
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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><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
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<author><name sortKey="Byun, Young Ho" sort="Byun, Young Ho" uniqKey="Byun Y" first="Young Ho" last="Byun">Young Ho Byun</name>
<affiliation><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Park, Soree" sort="Park, Soree" uniqKey="Park S" first="Soree" last="Park">Soree Park</name>
<affiliation><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</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:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</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><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Won, Juhee" sort="Won, Juhee" uniqKey="Won J" first="Juhee" last="Won">Juhee Won</name>
<affiliation><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</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:affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</nlm:affiliation>
</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:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Lee, Ah Ram" sort="Lee, Ah Ram" uniqKey="Lee A" first="Ah Ram" last="Lee">Ah Ram Lee</name>
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</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><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</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:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</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:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sim, Heewoo" sort="Sim, Heewoo" uniqKey="Sim H" first="Heewoo" last="Sim">Heewoo Sim</name>
<affiliation><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</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:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Jae, Byeongjune" sort="Jae, Byeongjune" uniqKey="Jae B" first="Byeongjune" last="Jae">Byeongjune Jae</name>
<affiliation><nlm:affiliation>Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Son, Ahyun" sort="Son, Ahyun" uniqKey="Son A" first="Ahyun" last="Son">Ahyun Son</name>
<affiliation><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Kim, Paul" sort="Kim, Paul" uniqKey="Kim P" first="Paul" last="Kim">Paul Kim</name>
<affiliation><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Yu, Jieun" sort="Yu, Jieun" uniqKey="Yu J" first="Jieun" last="Yu">Jieun Yu</name>
<affiliation><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</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><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</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><nlm:affiliation>Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.</nlm:affiliation>
</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:affiliation>Department of Applied Chemistry, Kyung Hee University, Yongin, Korea.</nlm:affiliation>
</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><nlm:affiliation>Department of Microbiology, School of Medicine, Konkuk University, Seoul, Korea.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Park, Yeong Min" sort="Park, Yeong Min" uniqKey="Park Y" first="Yeong-Min" last="Park">Yeong-Min Park</name>
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</affiliation>
</author>
<author><name sortKey="Seong, Baik L" sort="Seong, Baik L" uniqKey="Seong B" first="Baik L" last="Seong">Baik L. Seong</name>
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</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>
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<term>Animals</term>
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<term>History, 20th Century</term>
<term>Humans</term>
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<term>Influenza, Human (virology)</term>
<term>Interferons (metabolism)</term>
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<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Orthomyxoviridae (metabolism)</term>
<term>Orthomyxoviridae (pathogenicity)</term>
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<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>
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<term>Viral Proteins</term>
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<term>Mice</term>
<term>Mice, Inbred BALB C</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>
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<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>
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