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Quantitative Proteomics of Uukuniemi Virus-host Cell Interactions Reveals GBF1 as Proviral Host Factor for Phleboviruses
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).ORCID-id: 0000-0001-8123-3292
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2019 (Engelska)Ingår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, nr 12, s. 2401-2417Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Novel tick-borne phleboviruses in the Phenuiviridae family, which are highly pathogenic in humans and all closely related to Uukuniemi virus (UUKV), have recently emerged on different continents. How phleboviruses assemble, bud, and exit cells remains largely elusive. Here, we performed high-resolution, label-free mass spectrometry analysis of UUKV immunoprecipitated from cell lysates and identified 39 cellular partners interacting with the viral envelope glycoproteins. The importance of these host factors for UUKV infection was validated by silencing each host factor by RNA interference. This revealed Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1), a guanine nucleotide exchange factor resident in the Golgi, as a critical host factor required for the UUKV life cycle. An inhibitor of GBF1, Golgicide A, confirmed the role of the cellular factor in UUKV infection. We could pinpoint the GBF1 requirement to UUKV replication and particle assembly. When the investigation was extended to viruses from various positive and negative RNA viral families, we found that not only phleboviruses rely on GBF1 for infection, but also Flavi-, Corona-, Rhabdo-, and Togaviridae. In contrast, silencing or blocking GBF1 did not abrogate infection by the human adenovirus serotype 5 and immunodeficiency retrovirus type 1, the replication of both requires nuclear steps. Together our results indicate that UUKV relies on GBF1 for viral replication, assembly and egress. This study also highlights the proviral activity of GBF1 in the infection by a broad range of important zoonotic RNA viruses. Ticks are important vectors of infectious emerging diseases and tick-borne phleboviruses represent a growing threat to humans globally. We employed here a high-resolution, label-free mass spectrometry and RNA interference screen approach to reveal the host cell protein GBF1 as a proviral factor, not only for tick-borne phleboviruses, but also for many other important zoonotic RNA viruses. This study lays the basis for the development of innovative antiviral strategies against a broad range of human pathogenic viruses.

Ort, förlag, år, upplaga, sidor
American Society for Biochemistry and Molecular Biology, 2019. Vol. 18, nr 12, s. 2401-2417
Nyckelord [en]
Viruses, glycoproteins, affinity proteomics, label-free quantification, peptide mass fingerprinting, assembly, egress, GBF1, replication, Uukuniemi
Nationell ämneskategori
Mikrobiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-166821DOI: 10.1074/mcp.RA119.001631ISI: 000501288700005PubMedID: 31570497Scopus ID: 2-s2.0-85075963172OAI: oai:DiVA.org:umu-166821DiVA, id: diva2:1382488
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseVetenskapsrådet, 2018-05851Tillgänglig från: 2020-01-03 Skapad: 2020-01-03 Senast uppdaterad: 2023-11-28Bibliografiskt granskad

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Nilsson, EmmaLindquist, RichardÖverby, Anna K.Gerold, Gisa

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Nilsson, EmmaLindquist, RichardÖverby, Anna K.Lozach, Pierre-YvesGerold, Gisa
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Avdelningen för virologiMolekylär Infektionsmedicin, Sverige (MIMS)Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)
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Molecular & Cellular Proteomics
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