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dc.contributor.authorZhang, Zhenlu
dc.contributor.authorHe, Guijuan
dc.contributor.authorHan, Gil-Soo
dc.contributor.authorZhang, Jiantao
dc.contributor.authorCatanzaro, Nicholas
dc.contributor.authorDiaz, Arturo
dc.contributor.authorWu, Zujian
dc.contributor.authorCarman, George M
dc.contributor.authorXie, Lianhui
dc.contributor.authorWang, Xiaofeng
dc.date.accessioned2018-06-13T22:28:48Z
dc.date.available2018-06-13T22:28:48Z
dc.date.issued2018-04
dc.identifier.citationZhang Z, He G, Han G-S, Zhang J, Catanzaro N, Diaz A, et al. (2018) Host Pah1p phosphatidate phosphatase limits viral replication by regulating phospholipid synthesis. PLoS Pathog 14(4): e1006988. https://doi.org/10.1371/journal.ppat.1006988en_US
dc.identifier.issn1553-7374
dc.identifier.pmid29649282
dc.identifier.doi10.1371/journal.ppat.1006988
dc.identifier.urihttp://hdl.handle.net/10150/627965
dc.description.abstractReplication of positive-strand RNA viruses [(+)RNA viruses] takes place in membrane-bound viral replication complexes (VRCs). Formation of VRCs requires virus-mediated manipulation of cellular lipid synthesis. Here, we report significantly enhanced brome mosaic virus (BMV) replication and much improved cell growth in yeast cells lacking PAH1 (pah1Δ), the sole yeast ortholog of human LIPIN genes. PAH1 encodes Pah1p (phosphatidic acid phosphohydrolase), which converts phosphatidate (PA) to diacylglycerol that is subsequently used for the synthesis of the storage lipid triacylglycerol. Inactivation of Pah1p leads to altered lipid composition, including high levels of PA, total phospholipids, ergosterol ester, and free fatty acids, as well as expansion of the nuclear membrane. In pah1Δ cells, BMV replication protein 1a and double-stranded RNA localized to the extended nuclear membrane, there was a significant increase in the number of VRCs formed, and BMV genomic replication increased by 2-fold compared to wild-type cells. In another yeast mutant that lacks both PAH1 and DGK1 (encodes diacylglycerol kinase converting diacylglycerol to PA), which has a normal nuclear membrane but maintains similar lipid compositional changes as in pah1Δ cells, BMV replicated as efficiently as in pah1Δ cells, suggesting that the altered lipid composition was responsible for the enhanced BMV replication. We further showed that increased levels of total phospholipids play an important role because the enhanced BMV replication required active synthesis of phosphatidylcholine, the major membrane phospholipid. Moreover, overexpression of a phosphatidylcholine synthesis gene (CHO2) promoted BMV replication. Conversely, overexpression of PAH1 or plant PAH1 orthologs inhibited BMV replication in yeast or Nicotiana benthamiana plants. Competing with its host for limited resources, BMV inhibited host growth, which was markedly alleviated in pah1Δ cells. Our work suggests that Pah1p promotes storage lipid synthesis and thus represses phospholipid synthesis, which in turn restricts both viral replication and cell growth during viral infection.en_US
dc.description.sponsorshipChina Scholarship Council; National Institute of Health [GM028140]; National Science Foundation [IOS-1645740]; Virginia Agricultural Experiment Station; Hatch Program of National Institute of Food and Agriculture, United States Department of Agriculture; NIH-NIGMS [P20 GM103446]; NSF [IIA-1301765]; State of Delawareen_US
dc.language.isoenen_US
dc.publisherPUBLIC LIBRARY SCIENCEen_US
dc.relation.urlhttp://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006988en_US
dc.rights© 2018 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.en_US
dc.titleHost Pah1p phosphatidate phosphatase limits viral replication by regulating phospholipid synthesis.en_US
dc.typeArticleen_US
dc.contributor.departmentUniv Arizona, Dept Pharmacol & Toxicolen_US
dc.identifier.journalPLOS PATHOGENSen_US
dc.description.noteOpen access journal.en_US
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitlePLoS pathogens
refterms.dateFOA2018-06-13T22:28:49Z


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