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Cell Type Variability in the Incorporation of Lipids in the Dengue Virus Virion.

ABSTRACT: A lipid bilayer produced from the host membrane makes up around 20% of the weight of the dengue virus (DENV) virion and is crucial for virus entry. Despite its significance, the virion's lipid composition is still poorly understood. In tandem with lipid profiles of the cells utilised to generate the virions, this work determined a partial lipid profile of DENV virions derived from two cell lines (C6/36 and LLC-MK₂). The results showed distinctive profiles between the two cell types. In the mammalian LLC-MK₂ cells, 30.8% (73/237 identified lipid species; 31 upregulated, 42 downregulated) of lipid species were altered in response to infection, whilst in insect C6/36 cells only 12.0% (25/208; 19 upregulated, 6 downregulated) of lipid species showed alterations in response to infection. For virions from LLC-MK₂ cells, 14 lipids were detected specifically in virions with a further seven lipids being enriched (over mock controls). For virions from C6/36 cells, 43 lipids were detected that were not seen in mock preparations, with a further 16 being specifically enriched (over mock control). These results provide the first lipid description of DENV virions produced in mammalian and mosquito cells, as well as the lipid changes in the corresponding infected cells.

SUBMITTER: Hitakarun A

PROVIDER: S-EPMC9698084 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Cell Type Variability in the Incorporation of Lipids in the Dengue Virus Virion.

Hitakarun Atitaya A Williamson Maia Kavanagh MK Yimpring Nathamon N Sornjai Wannapa W Wikan Nitwara N Arthur Christopher J CJ Pompon Julien J Davidson Andrew D AD Smith Duncan R DR

Viruses 20221119 11

A lipid bilayer produced from the host membrane makes up around 20% of the weight of the dengue virus (DENV) virion and is crucial for virus entry. Despite its significance, the virion's lipid composition is still poorly understood. In tandem with lipid profiles of the cells utilised to generate the virions, this work determined a partial lipid profile of DENV virions derived from two cell lines (C6/36 and LLC-MK<sub>2</sub>). The results showed distinctive profiles between the two cell types. I ...[more]

PMID: 36423175

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Project description:Alphaherpesvirus envelope glycoprotein N (gN) and gM form a covalently linked complex. Bovine herpesvirus type 1 (BHV-1) UL49.5 (a gN homolog) contains two predicted cysteine residues, C42 and C78. The C42 is highly conserved among the alphaherpesvirus gN homologs (e.g., herpes simplex virus 1 and pseudorabies virus). To identify which cysteine residue is required for the formation of the UL49.5/gM complex and to characterize the functional significance of the UL49.5/gM complex, we constructed and analyzed C42S and C78S substitution mutants in either a BHV-1 wild type (wt) or BHV-1 UL49.5 cytoplasmic tail-null (CT-null) virus background. The results demonstrated that BHV-1 UL49.5 residue C42 but not C78 was essential for the formation of the covalently linked functional UL49.5/gM complex, gM maturation in the Golgi compartment, and efficient cell-to-cell spread of the virus. Interestingly, the C42S and CT-null mutations separately did not affect mutant UL49.5 virion incorporation. However, when both of the mutations were introduced simultaneously, the UL49.5 C42S/CT-null protein virion incorporation was severely reduced. Incidentally, the anti-VP22 antibody coimmunoprecipitated the UL49.5 C42S/CT-null mutant protein at a noticeably reduced level compared to that of the individual UL49.5 C42S and CT-null mutant proteins. As expected, in a dual UL49.5 C42S/VP22Δ virus with deletion of VP22 (VP22Δ), the UL49.5 C42S virion incorporation was also severely reduced while in a gMΔ virus, UL49.5 virion incorporation was affected only slightly. Together, these results suggested that UL49.5 virion incorporation is mediated redundantly, by both UL49.5/gM functional complex and VP22, through a putative gM-independent novel UL49.5 and VP22 interaction.IMPORTANCE Bovine herpesvirus 1 (BHV-1) envelope protein UL49.5 is an important virulence determinant because it downregulates major histocompatibility complex class I (MHC-I). UL49.5 also forms a covalently linked complex with gM. The results of this study demonstrate that UL49.5 regulates gM maturation and virus cell-to-cell spread since gM maturation in the Golgi compartment depends on covalently linked UL49.5/gM complex. The results also show that the UL49.5 residue cysteine 42 (C42) mediates the formation of the covalently linked UL49.5-gM interaction. Furthermore, a C42S mutant virus in which UL49.5 cannot interact with gM has defective cell-to-cell spread. Interestingly, UL49.5 also interacts with the tegument protein VP22 via its cytoplasmic tail (CT). The putative UL49.5 CT-VP22 interaction is essential for a gM-independent UL49.5 virion incorporation and is revealed when UL49.5 and gM are not linked. Therefore, UL49.5 virion incorporation is mediated by UL49.5-gM complex interaction and through a gM-independent interaction between UL49.5 and VP22.

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Dataset Information

Cell Type Variability in the Incorporation of Lipids in the Dengue Virus Virion.

Publications

Cell Type Variability in the Incorporation of Lipids in the Dengue Virus Virion.

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