Quantitative Proteomics of Uukuniemi Virus-host Cell Interactions Reveals GBF1 as Proviral Host Factor for Phleboviruses

Uckeley, Zina M.; Moeller, Rebecca; Kühn, Lars I.; Nilsson, Emma; Robens, Claudia; Laßwitz, Lisa; Lindqvist, Richard; Lenman, Annasara; Passos, Vânia; Voß, Yannik; Sommerauer, Christian; Kampmann, Martin; Goffinet, Christine; Meissner, Felix; Överby, Anna K.; Lozach, Pierre‐Yves

doi:10.1074/mcp.ra119.001631

Cited by 17 publications

(14 citation statements)

References 79 publications

(85 reference statements)

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“…The strong enrichment of Chol, SM, and PE P in the viral envelope supports a budding of viral particles from post ER/post cis Golgi compartments. This is consistent with the accumulation of the UUKV glycoproteins Gn and Gc more in trans in the Golgi network, from where virions bud (Overby et al, 2006; Uckeley et al, 2019).…”

Section: Discussionsupporting

confidence: 84%

The glycolipid GlcCer is recruited into the viral envelope to promote phenuivirus binding to host cells

Uckeley

Mazelier

Luechtenborg

et al. 2022

Preprint

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Virus-receptor interactions largely contribute to the tropism and outcome of an infection. Here, we found that the glycolipid glucosylceramide (GlcCer) is a major component of Uukuniemi phenuivirus and allows viral binding to host cells. A lipidomic analysis with mass spectrometry revealed the lipidome of UUKV particles and indicated that GlcCer was enriched in both infected cells and viral particles. In addition, the infectivity of UUKV depended on the conversion of ceramide (Cer) into GlcCer in the Golgi network of producer cells. In contrast, depletion of GlcCer in virions profoundly impaired the attachment of UUKV and other related viruses to target cells. Furthermore, competing GlcCer ligands prevented virus binding to various cell types. Altogether, our results demonstrate that glycolipids are essential structural determinants of the virions necessary for virus attachment to host cells and have strong implications for future work on the identification of virus receptors.

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Section: Discussionsupporting

confidence: 84%

The glycolipid GlcCer is recruited into the viral envelope to promote phenuivirus binding to host cells

Uckeley

Mazelier

Luechtenborg

et al. 2022

Preprint

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“…UUKV is not associated with any disease in humans. It is a validated biosafety level (BSL)-2 surrogate that enabled major advances in many aspects of the cell life cycle of phenuiviruses with a higher biosafety classification, such as receptors, cell entry, and assembly [ 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Entry of Phenuiviruses into Mammalian Host Cells

Koch

Xin

Tischler

et al. 2021

Viruses

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Phenuiviridae is a large family of arthropod-borne viruses with over 100 species worldwide. Several cause severe diseases in both humans and livestock. Global warming and the apparent geographical expansion of arthropod vectors are good reasons to seriously consider these viruses potential agents of emerging diseases. With an increasing frequency and number of epidemics, some phenuiviruses represent a global threat to public and veterinary health. This review focuses on the early stage of phenuivirus infection in mammalian host cells. We address current knowledge on each step of the cell entry process, from virus binding to penetration into the cytosol. Virus receptors, endocytosis, and fusion mechanisms are discussed in light of the most recent progress on the entry of banda-, phlebo-, and uukuviruses, which together constitute the three prominent genera in the Phenuiviridae family.

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“…This is the first report of COPI complex and Arf1 involvement in the replication cycle of a bunyavirus. Recently, Uukuneimi virus, a member of the Phenuiviridae family within the Bunyavirales order was shown to require the activity of GBF1 ( 41 ), a GEF required for Arf1 activation, and thus it is possible that our findings reported here relate to a common functional requirement of COPI vesicle formation for the Bunyavirales . Components of the COPI complex have been implicated in the growth of many viruses, with proposed involvement in several distinct life cycle stages, including entry ( 42 – 47 ), gene expression ( 48 – 51 ), virus assembly, and egress ( 39 , 52 , 53 ).…”

Section: Discussionmentioning

confidence: 85%

Hazara Nairovirus Requires COPI Components in both Arf1-Dependent and Arf1-Independent Stages of Its Replication Cycle

Fuller

Álvarez‐Rodríguez

Todd

et al. 2020

J Virol

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Hazara nairovirus (HAZV) is an enveloped tri-segmented negative strand RNA virus classified within the Nairoviridae family of the Bunyavirales order, and a member of the same subtype as Crimean-Congo hemorrhagic fever virus, responsible for fatal human disease. Nairoviral subversion of cellular trafficking pathways to permit viral entry, gene expression, assembly and egress is poorly understood. Here, we generated a recombinant HAZV expressing eGFP and used live-cell fluorescent imaging to screen an siRNA library targeting genes involved in cellular trafficking networks, the first such screen for a nairovirus. The screen revealed prominent roles for subunits of the coat protein 1 (COPI)-vesicle coatomer, which regulates retrograde trafficking of cargo between the Golgi and ER as well as intra-Golgi transport. We showed the requirement of COPI-coatomer subunits impacted at least two stages of the HAZV replication cycle; an early stage prior to and including gene expression, and also a later stage during assembly and egress of infectious virus, with COPI-knockdown reducing titres by approximately 1000-fold. Treatment of HAZV-infected cells with brefeldin-A (BFA), an inhibitor of Arf1 activation required for COPI coatomer formation, revealed this late COPI-dependent stage was Arf1-dependent, consistent with the established role of Arf1 in COPI vesicle formation. In contrast, the early COPI-dependent stage was Arf1-independent, with neither BFA treatment nor siRNA-mediated ARF1 knockdown affecting HAZV gene expression. HAZV exploitation of COPI components in a non-canonical Arf1-independent process suggests COPI coatomer components may perform roles unrelated to vesicle formation, adding further complexity to our understanding of cargo-mediated transport. IMPORTANCE Nairoviruses are tick-borne enveloped RNA viruses that include several pathogens responsible for fatal disease in humans and animals. Here, we analysed host genes involved in trafficking networks to examine their involvement in nairovirus replication. We revealed important roles for genes that express multiple components of the COPI complex, which regulates transport of Golgi-resident cargos. COPI components influenced at least two stages of the nairovirus replication cycle; an early stage prior to and including gene expression, and also a later stage during assembly of infectious virus, with COPI-knockdown reducing titres by approximately 1000-fold. Importantly, while the late stage was Arf1-dependent, as expected for canonical COPI vesicle formation, the early stage was found to be Arf1-independent, suggestive of a previously unreported function of COPI unrelated to vesicle formation. Collectively, these data improve our understanding of nairovirus host-pathogen interactions, and suggest a new Arf1-independent role for components of the COPI coatomer complex.

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Quantitative Proteomics of Uukuniemi Virus-host Cell Interactions Reveals GBF1 as Proviral Host Factor for Phleboviruses

Cited by 17 publications

References 79 publications

The glycolipid GlcCer is recruited into the viral envelope to promote phenuivirus binding to host cells

The glycolipid GlcCer is recruited into the viral envelope to promote phenuivirus binding to host cells

Entry of Phenuiviruses into Mammalian Host Cells

Hazara Nairovirus Requires COPI Components in both Arf1-Dependent and Arf1-Independent Stages of Its Replication Cycle

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