Mechanisms of phosphatidylserine influence on viral production: A computational model of Ebola virus matrix protein assembly

Liu, Xiao; Pappas, Ethan J; Husby, Monica L.; Motsa, Balindile B.; Stahelin, Robert V.; Pienaar, Elsje

doi:10.1016/j.jbc.2022.102025

Cited by 6 publications

(9 citation statements)

References 81 publications

(118 reference statements)

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“…In fact, VP40 effectively binds and oligomerizes on PS‐containing membranes with compositions close to the PS content of the PM inner leaflet. This is consistent with a recent computational study that demonstrated higher PS levels resulted in a higher VLP budding rate (Liu et al , 2022). In contrast, PS concentrations below 15 mol% did not provide robust affinity and oligomerization compared with those with 22 mol% PS and greater.…”

Section: Discussionsupporting

confidence: 93%

Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding

et al. 2022

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Phosphatidylserine (PS) is 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 and subsequent virus budding and entry. To gain mechanistic insight into fendiline inhibition of EBOV replication, multiple in vitro assays were run including imaging, viral budding and viral entry assays. Fendiline lowers PS content in mammalian cells and PS in the plasma membrane, where the ability of VP40 to form new virus particles is greatly lower. Further, particles that form from fendiline‐treated cells have altered particle morphology and cannot significantly infect/enter cells. These complementary studies reveal the mechanism by which EBOV matrix protein clusters 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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Section: Discussionsupporting

confidence: 93%

Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding

et al. 2022

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“…We developed our NP-VP40 model (Eqs. ( 1 )–( 27 )) based on our previous model that was composed of VP40 interactions alone 24 , 25 . Here, we explicitly incorporated the assembly of NP IBs and the assembly and budding of VP40 filaments (with or without NP IBs).…”

Section: Resultsmentioning

confidence: 99%

“…Further details on model construction and equations can be found in the Materials and Methods section. Figure was generated in Microsoft Powerpoint using elements from our prior work 24 , 25 . …”

Section: Resultsmentioning

confidence: 99%

“…Mathematical modeling is a valuable tool to provide such quantitative insights into complex biological systems 23 . We previously developed the first ODE-based model of VP40 assembly and budding at the intracellular level 24 , 25 . Our model suggested several mechanisms of VP40 and phosphatidylserine (PS) interactions regarding the formation of VLPs, such as the influence of PS on VLP egress.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we build on this prior work with VP40 24 , 25 to construct an ODE-based model of EBOV NP-VP40 interactions, assembly and budding at the subcellular level. We use this model to (a) test which interactions between NP and VP40 can give rise to the experimentally observed impacts of co-expression, as well as (b) quantify the impact of NP on VP40 VLP production.…”

Section: Introductionmentioning

confidence: 99%

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Impact of Ebola virus nucleoprotein on VP40 virus-like particle production: a computational approach

Liu,

Stahelin,

Pienaar

2024

Commun Biol

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Ebola virus (EBOV) matrix protein VP40 can assemble and bud as virus-like particles (VLPs) when expressed alone in mammalian cells. Nucleoprotein (NP) could be recruited to VLPs as inclusion body (IB) when co-expressed, and increase VLP production. However, the mechanism behind it remains unclear. Here, we use a computational approach to study NP-VP40 interactions. Our simulations indicate that NP may enhance VLP production through stabilizing VP40 filaments and accelerating the VLP budding step. Further, both the relative timing and amount of NP expression compared to VP40 are important for the effective production of IB-containing VLPs. We predict that relative NP/VP40 expression ratio and time are important for efficient production of IB-containing VLPs. We conclude that disrupting the expression timing and amount of NP and VP40 could provide new avenues to treat EBOV infection. This work provides quantitative insights into EBOV proteins interactions and how virion generation and drug efficacy could be influenced.

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Evaluation of Fendiline Treatment in VP40 System with Nucleation-Elongation Process: A Computational Model of Ebola Virus Matrix Protein Assembly

Liu

Husby

Stahelin

et al. 2023

Preprint

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Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and requirement of biosafety level-4 (BSL-4) laboratories hinders experimental work to advance our understanding of EBOV and evaluation of treatment. In this work, we use a computational model to study the assembly and budding process of EBOV and evaluate the effect of fendiline on these processes. Our results indicate that the assembly of VP40 filaments may follow the nucleation-elongation theory, as it is critical to maintain a pool of VP40 dimer for the maturation and production of virus-like particles (VLPs). We further find that the nucleation-elongation process can also be influenced by phosphatidylserine (PS), which can complicate the efficacy of fendiline, a drug that lowers cellular PS levels. We observe that fendiline may increase VLP production at earlier time points (24 h) and under low concentrations (≤ 2 μM). But this effect is transient and does not change the conclusion that fendiline generally decreases VLP production. We also conclude that fendiline can be more efficient at the stage of VLP budding relative to earlier phases. Combination therapy with a VLP budding step-targeted drug may further increase the treatment efficiency of fendiline. Finally, we also show that fendiline has higher efficacy when VP40 expression is high. While these are single-cell level results based on the VP40 system, it points out a potential way of fendiline application affecting EBOV assembly, which can be further tested in experimental studies with multiple EBOV proteins or live virus.

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Mechanisms of phosphatidylserine influence on viral production: A computational model of Ebola virus matrix protein assembly

Cited by 6 publications

References 81 publications

Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding

Phosphatidylserine clustering by the Ebola virus matrix protein is a critical step in viral budding

Impact of Ebola virus nucleoprotein on VP40 virus-like particle production: a computational approach

Evaluation of Fendiline Treatment in VP40 System with Nucleation-Elongation Process: A Computational Model of Ebola Virus Matrix Protein Assembly

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