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Article: Cell Cycle-independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection

TitleCell Cycle-independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection
Authors
KeywordsCell cycle
G1/S cyclin
Influenza
Protein degradation
Protein-protein interaction
M2
Cell cycle arrest
Cyclin D3
Restriction factor
Issue Date2017
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2017, v. 292 n. 12, p. 5070-5088 How to Cite?
AbstractTo identify new host factors that modulate the replication of influenza A virus, we performed a yeast two-hybrid screen using the cytoplasmic tail of matrix protein 2 from the highly pathogenic H5N1 strain. The screen revealed a high-score interaction with cyclin D3, a key regulator of cell cycle early G1 phase. M2-cyclin D3 interaction was validated through GST pull-down and recapitulated in influenza A/WSN/33-infected cells. Knockdown of Ccnd3 by small interfering RNA significantly enhanced virus progeny titers in cell culture supernatants. Interestingly, the increase in virus production was due to cyclin D3 deficiency per se and not merely a consequence of cell cycle deregulation. A combined knockdown of Ccnd3 and Rb1, which rescued cell cycle progression into S phase, failed to normalize virus production. Infection by influenza A virus triggered redistribution of cyclin D3 from the nucleus to the cytoplasm, followed by its proteasomal degradation. When overexpressed in HEK 293T cells, cyclin D3 impaired binding of M2 with M1, which is essential for proper assembly of progeny virions, lending further support to its role as a putative restriction factor. Our study describes the identification and characterization of cyclin D3 as a novel interactor of influenza A virus M2 protein. We hypothesize that competitive inhibition of M1-M2 interaction by cyclin D3 impairs infectious virion formation and results in attenuated virus production. In addition, we provide mechanistic insights into the dynamic interplay of influenza virus with the host cell cycle machinery during infection.
Persistent Identifierhttp://hdl.handle.net/10722/239499
ISSN
2019 Impact Factor: 4.238
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorFan, Y-
dc.contributor.authorMok, CK-
dc.contributor.authorChan, MCW-
dc.contributor.authorZhang, Y-
dc.contributor.authorNal, B-
dc.contributor.authorKien, F-
dc.contributor.authorBruzzone, R-
dc.contributor.authorSanyal, S-
dc.date.accessioned2017-03-21T09:14:58Z-
dc.date.available2017-03-21T09:14:58Z-
dc.date.issued2017-
dc.identifier.citationJournal of Biological Chemistry, 2017, v. 292 n. 12, p. 5070-5088-
dc.identifier.issn0021-9258-
dc.identifier.urihttp://hdl.handle.net/10722/239499-
dc.description.abstractTo identify new host factors that modulate the replication of influenza A virus, we performed a yeast two-hybrid screen using the cytoplasmic tail of matrix protein 2 from the highly pathogenic H5N1 strain. The screen revealed a high-score interaction with cyclin D3, a key regulator of cell cycle early G1 phase. M2-cyclin D3 interaction was validated through GST pull-down and recapitulated in influenza A/WSN/33-infected cells. Knockdown of Ccnd3 by small interfering RNA significantly enhanced virus progeny titers in cell culture supernatants. Interestingly, the increase in virus production was due to cyclin D3 deficiency per se and not merely a consequence of cell cycle deregulation. A combined knockdown of Ccnd3 and Rb1, which rescued cell cycle progression into S phase, failed to normalize virus production. Infection by influenza A virus triggered redistribution of cyclin D3 from the nucleus to the cytoplasm, followed by its proteasomal degradation. When overexpressed in HEK 293T cells, cyclin D3 impaired binding of M2 with M1, which is essential for proper assembly of progeny virions, lending further support to its role as a putative restriction factor. Our study describes the identification and characterization of cyclin D3 as a novel interactor of influenza A virus M2 protein. We hypothesize that competitive inhibition of M1-M2 interaction by cyclin D3 impairs infectious virion formation and results in attenuated virus production. In addition, we provide mechanistic insights into the dynamic interplay of influenza virus with the host cell cycle machinery during infection.-
dc.languageeng-
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistry-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectCell cycle-
dc.subjectG1/S cyclin-
dc.subjectInfluenza-
dc.subjectProtein degradation-
dc.subjectProtein-protein interaction-
dc.subjectM2-
dc.subjectCell cycle arrest-
dc.subjectCyclin D3-
dc.subjectRestriction factor-
dc.titleCell Cycle-independent Role of Cyclin D3 in Host Restriction of Influenza Virus Infection-
dc.typeArticle-
dc.identifier.emailFan, Y: ivonnayf@hku.hk-
dc.identifier.emailMok, CK: ch02mkp@hkucc.hku.hk-
dc.identifier.emailChan, MCW: mchan@hku.hk-
dc.identifier.emailZhang, Y: yufish@hku.hk-
dc.identifier.emailBruzzone, R: bruzzone@hkucc.hku.hk-
dc.identifier.emailSanyal, S: sanyal@hku.hk-
dc.identifier.authorityMok, CK=rp01805-
dc.identifier.authorityChan, MCW=rp00420-
dc.identifier.authorityBruzzone, R=rp01442-
dc.identifier.authoritySanyal, S=rp01794-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1074/jbc.M117.776112-
dc.identifier.pmid28130444-
dc.identifier.pmcidPMC5377818-
dc.identifier.hkuros271563-
dc.identifier.volume292-
dc.identifier.issue12-
dc.identifier.spage5070-
dc.identifier.epage5088-
dc.identifier.isiWOS:000397590400027-
dc.publisher.placeUnited States-

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