Lipid-specific oligomerization of the Marburg virus matrix protein VP40 is regulated by two distinct interfaces for virion assembly

Amiar, Souad; Husby, Monica L.; Wijesinghe, Kaveesha J.; Angel, Stephanie; Bhattarai, Nisha; Gerstman, Bernard S.; Chapagain, Prem P.; Li, Sheng; Stahelin, Robert V.

doi:10.1016/j.jbc.2021.100796

Cited by 15 publications

(25 citation statements)

References 63 publications

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“…mVP40 acts as a charge sensor, its binding to the plasma membrane is dependent on the anionic charge density of the plasma membrane and when this charge density is neutralized there is a dramatic reduction in mVP40 localization [ 17 ]. Despite the promiscuity in mVP40 lipid binding, proper oligomerization of mVP40 dimers is mediated by PS and PI(4,5)P 2 where PS is required for NTD–NTD interactions and PI(4,5)P 2 for CTD–CTD interactions [ 18 ]. As with eVP40, mVP40 has two loop regions in the CTD that contain cationic residues and form a lipid binding basic patch.…”

Section: Filovirus Assembly and Buddingmentioning

confidence: 99%

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Lipid–protein interactions in virus assembly and budding from the host cell plasma membrane

Motsa

Stahelin

2021

Biochemical Society Transactions

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Lipid enveloped viruses contain a lipid bilayer coat that protects their genome to help facilitate entry into the new host cell. This lipid bilayer comes from the host cell which they infect. After viral replication, the mature virion hijacks the host cell plasma membrane where it is then released to infect new cells. This process is facilitated by the interaction between phospholipids that make up the plasma membrane and specialized viral matrix proteins. This step in the viral lifecycle may represent a viable therapeutic strategy for small molecules that aim to block enveloped virus spread. In this review, we summarize the current knowledge on the role of plasma membrane lipid–protein interactions on viral assembly and budding.

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Section: Filovirus Assembly and Buddingmentioning

confidence: 99%

“…The dimeric eVP40 is trafficked to the inner leaflet of the plasma membrane [21]. Once the dimers associate with the PM, they undergo structural rearrangements into an array of dimer-dimer interactions [9,18,22]. The oligomers form extended VP40 matrix layers via CTD-CTD interactions.…”

Section: Vp40 Traffickingmentioning

confidence: 99%

Lipid–protein interactions in virus assembly and budding from the host cell plasma membrane

Motsa

Stahelin

2021

Biochemical Society Transactions

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“…12:0 dihydrosphingomyelin (DH-SM (d18:0/12:0), Avanti Polar Lipids, 860683) was prepared in ethanol and used to treated HEK293 cells at a final concentration of 2.5 μM for 3 hours at 37°C (adapted from ( 109)). Laurdan treatments were performed as described previously (71).…”

Section: Methodsmentioning

confidence: 99%

Integrity of membrane fluidity and fatty acid environment are necessary for Ebola virus VP40 assembly and release of viral particles

Amiar

Johnson

Husby

et al. 2022

Preprint

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Plasma membrane (PM) domains and order phases have been shown to play a key role in the assembly, release, and entry of several lipid-enveloped viruses. In the present study, we provide a mechanistic understanding of the Ebola virus (EBOV) matrix protein VP40 interaction with PM lipids and their effect on VP40 oligomerization, a crucial step for viral assembly and budding. VP40 matrix formation is sufficient to induce changes in the PM fluidity. We demonstrate that the distance between the lipid headgroups, the fatty acid tail saturation and the order between the two leaflets are important factors for the stability of VP40 binding and oligomerization at the PM. Use of FDA-approved drugs (dibucaine, propranolol and trifluoperazine) to fluidize the plasma membrane, destabilizes the viral matrix assembly leading to a reduction in budding efficiency. Lastly, we show that VP40 can tether and cluster lipid vesicles upon protein enrichment at the membrane. This is a new characteristic of the protein, and it opens the door to new avenues of exploration to deepen our understanding of VP40 host interactions and EBOV assembly. Indeed, our findings support a complex assembly mechanism of the EBOV viral matrix that reaches beyond lipid headgroup specificity using ordered PM lipid regions independent of cholesterol.

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“…EGFP, EGFP-eVP40 and EGFP-WE/A-eVP40 were prepared as described previously (Adu-Gyamfi et al , 2012; Johnson et al , 2016). GFP-K224A-eVP40 was prepared by site directed mutagenesis (Johnson et al , 2018) GFP-mVP40 was used as described previously (Wijesinghe & Stahelin 2015; Amiar et al , 2021). The GFP-LactC2 plasmid was a kind gift from Sergio Grinstein (University of Toronto).…”

Section: Methodsmentioning

confidence: 99%

The Ebola virus matrix protein clusters phosphatidylserine, a critical step in viral budding

Amiar

et al. 2021

Preprint

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Phosphatidylserine (PS) has been shown to be a critical lipid factor in the assembly and spread of numerous lipid enveloped viruses. Here, we describe the ability of the Ebola virus (EBOV) matrix protein eVP40 to induce clustering of PS and promote viral budding in vitro, as well as the ability of an FDA approved drug, fendiline, to reduce PS clustering subsequently reducing virus budding and entry. To gain mechanistic insight into fendiline inhibition of EBOV replication, multiple in vitro assays were employed including imaging, viral budding and viral entry assays. Fendiline reduced the PS content in mammalian cells and PS in the plasma membrane, reducing the ability of VP40 to form new virus particles. Further, particles that do form from fendiline treated cells have altered particle morphology and decreased infectivity capacity. These complementary studies reveal the mechanism by which filovirus matrix proteins cluster PS to enhance viral assembly, budding, and spread from the host cell while also laying the groundwork for fundamental drug targeting strategies.

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Lipid-specific oligomerization of the Marburg virus matrix protein VP40 is regulated by two distinct interfaces for virion assembly

Cited by 15 publications

References 63 publications

Lipid–protein interactions in virus assembly and budding from the host cell plasma membrane

Lipid–protein interactions in virus assembly and budding from the host cell plasma membrane

Integrity of membrane fluidity and fatty acid environment are necessary for Ebola virus VP40 assembly and release of viral particles

The Ebola virus matrix protein clusters phosphatidylserine, a critical step in viral budding

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