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Article: Minor changes in electrostatics robustly increase VP40 membrane binding, assembly, and budding of Ebola virus matrix protein derived virus-like particles.

Motsa, Balindile B / Sharma, Tej / Chapagain, Prem P / Stahelin, Robert V

bioRxiv : the preprint server for biology

2024

Abstract: Ebola virus (EBOV) is a filamentous negative-sense RNA virus which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it is important to get a detailed understanding of the virus lifecycle ...

Abstract	Ebola virus (EBOV) is a filamentous negative-sense RNA virus which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it is important to get a detailed understanding of the virus lifecycle to illuminate new drug targets. EBOV encodes for the matrix protein, VP40, which regulates assembly and budding of new virions from the inner leaflet of the host cell plasma membrane (PM). In this work we determine the effects of VP40 mutations altering electrostatics on PM interactions and subsequent budding. VP40 mutations that modify surface electrostatics affect viral assembly and budding by altering VP40 membrane binding capabilities. Mutations that increase VP40 net positive charge by one (e.g., Gly to Arg or Asp to Ala) increase VP40 affinity for phosphatidylserine (PS) and PI(4,5)P
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.30.578092
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Article ; Online: Evaluation of fendiline treatment in VP40 system with nucleation-elongation process: a computational model of Ebola virus matrix protein assembly.

Liu, Xiao / Husby, Monica / Stahelin, Robert V / Pienaar, Elsje

Microbiology spectrum

2024 Volume 12, Issue 4, Page(s) e0309823

Abstract: Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 laboratories hinder experimental work to advance our understanding of EBOV and the ... ...

Abstract	Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 laboratories hinder experimental work to advance our understanding of EBOV and the 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 in the context of fluctuating host membrane lipid levels. Our results demonstrate for the first time that the assembly of VP40 filaments may follow the nucleation-elongation theory, as this mechanism is critical to maintaining a pool of VP40 dimers for the maturation and production of virus-like particles (VLPs). We further find that this nucleation-elongation process is likely influenced by fluctuating phosphatidylserine (PS), which can complicate the efficacy of lipid-targeted therapies like fendiline, a drug that lowers cellular PS levels. Our results indicate that fendiline-induced PS reduction may actually increase VLP production at earlier time points (24 h) and under low fendiline concentrations (≤2 µM). However, this effect is transient and does not change the conclusion that fendiline generally decreases VLP production. In the context of fluctuating PS levels, we also conclude that fendiline can be more efficient at the late stage of VLP budding relative to earlier phases. Combination therapy with a VLP budding step-targeted drug may therefore further increase the treatment efficiency of fendiline. Finally, we also show that fendiline-induced PS reduction more effectively lowers VLP production when VP40 expression is high. Taken together, our results provide critical quantitative information on how fluctuating lipid levels (PS) affect EBOV assembly and egress and how this mechanism can be disrupted by lipid-targeting molecules like fendiline. Importance: Ebola virus (EBOV) infection can cause deadly hemorrhagic fever, which has a mortality rate of ~50%-90% without treatment. The recent outbreaks in Uganda and the Democratic Republic of the Congo illustrate its threat to human health. Though two antibody-based treatments were approved, mortality rates in the last outbreak were still higher than 30%. This can partly be due to the requirement of advanced medical facilities for current treatments. As a result, it is very important to develop and evaluate new therapies for EBOV infection, especially those that can be easily applied in the developing world. The significance of our research is that we evaluate the potential of lipid-targeted treatments in reducing EBOV assembly and egress. We achieved this goal using the VP40 system combined with a computational approach, which both saves time and lowers cost compared to traditional experimental studies and provides innovative new tools to study viral protein dynamics.
MeSH term(s)	Humans ; Hemorrhagic Fever, Ebola/drug therapy ; Ebolavirus/genetics ; Fendiline/metabolism ; Lipids ; Africa, Western
Chemical Substances	Fendiline (S253D559A8) ; Lipids
Language	English
Publishing date	2024-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.03098-23
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Article ; Online: The unmasking of the lipid binding face of sphingosine kinase 1.

Stahelin, Robert V

Journal of lipid research

2018 Volume 59, Issue 3, Page(s) 401–403

MeSH term(s)	Lipids ; Phosphotransferases (Alcohol Group Acceptor) ; Sphingosine
Chemical Substances	Lipids ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Sphingosine (NGZ37HRE42)
Language	English
Publishing date	2018-01-30
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.C083907
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Article ; Online: Role of phosphatidic acid lipids on plasma membrane association of the Ebola virus matrix protein VP40.

Cioffi, Michael D / Husby, Monica L / Gerstman, Bernard S / Stahelin, Robert V / Chapagain, Prem P

Biochimica et biophysica acta. Molecular and cell biology of lipids

2024 Volume 1869, Issue 3, Page(s) 159464

Abstract: The Ebola virus matrix protein VP40 is responsible for the formation of the viral matrix by localizing at the inner leaflet of the human plasma membrane (PM). Various lipid types, including PI(4,5) ... ...

Abstract	The Ebola virus matrix protein VP40 is responsible for the formation of the viral matrix by localizing at the inner leaflet of the human plasma membrane (PM). Various lipid types, including PI(4,5)P
MeSH term(s)	Humans ; Ebolavirus/metabolism ; Hemorrhagic Fever, Ebola/metabolism ; Cell Membrane/metabolism ; Molecular Dynamics Simulation ; Lipids/analysis
Chemical Substances	Lipids
Language	English
Publishing date	2024-02-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	60-7
ISSN	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2618 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbalip.2024.159464
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Article ; Online: Lipid-protein interactions in virus assembly and budding from the host cell plasma membrane.

Motsa, Balindile B / Stahelin, Robert V

Biochemical Society transactions

2021 Volume 49, Issue 4, Page(s) 1633–1641

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Cell Membrane/metabolism ; Host-Pathogen Interactions ; Lipids/chemistry ; Proteins/chemistry ; Virus Assembly
Chemical Substances	Lipids ; Proteins
Language	English
Publishing date	2021-08-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20200854
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Article ; Online: Negative-sense RNA viruses: An underexplored platform for examining virus-host lipid interactions.

Husby, Monica L / Stahelin, Robert V

Molecular biology of the cell

2021 Volume 32, Issue 20

Abstract: Viruses are pathogenic agents that can infect all varieties of organisms, including plants, animals, and humans. These microscopic particles are genetically simple as they encode a limited number of proteins that undertake a wide range of functions. ... ...

Abstract	Viruses are pathogenic agents that can infect all varieties of organisms, including plants, animals, and humans. These microscopic particles are genetically simple as they encode a limited number of proteins that undertake a wide range of functions. While structurally distinct, viruses often share common characteristics that have evolved to aid in their infectious life cycles. A commonly underappreciated characteristic of many deadly viruses is a lipid envelope that surrounds their protein and genetic contents. Notably, the lipid envelope is formed from the host cell the virus infects. Lipid-enveloped viruses comprise a diverse range of pathogenic viruses, which often lead to high fatality rates and many lack effective therapeutics and/or vaccines. This perspective primarily focuses on the negative-sense RNA viruses from the order Mononegavirales, which obtain their lipid envelope from the host plasma membrane. Specifically, the perspective highlights the common themes of host cell lipid and membrane biology necessary for virus replication, assembly, and budding.
MeSH term(s)	Animals ; Cell Membrane/metabolism ; Cell Membrane/virology ; Host-Pathogen Interactions/physiology ; Humans ; Lipid Metabolism/physiology ; Negative-Sense RNA Viruses/pathogenicity ; Negative-Sense RNA Viruses/physiology ; Viral Matrix Proteins/metabolism ; Virus Replication/physiology
Chemical Substances	Viral Matrix Proteins
Language	English
Publishing date	2021-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E19-09-0490
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Zs.A 2853: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Minor electrostatic changes robustly increase VP40 membrane binding, assembly, and budding of Ebola virus matrix protein derived virus-like particles.

Motsa, Balindile B / Sharma, Tej / Cioffi, Michael D / Chapagain, Prem P / Stahelin, Robert V

The Journal of biological chemistry

2024 Volume 300, Issue 5, Page(s) 107213

Abstract: Ebola virus (EBOV) is a filamentous negative-sense RNA virus, which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it is important to get a detailed understanding of the virus ... ...

Abstract	Ebola virus (EBOV) is a filamentous negative-sense RNA virus, which causes severe hemorrhagic fever. There are limited vaccines or therapeutics for prevention and treatment of EBOV, so it is important to get a detailed understanding of the virus lifecycle to illuminate new drug targets. EBOV encodes for the matrix protein, VP40, which regulates assembly and budding of new virions from the inner leaflet of the host cell plasma membrane (PM). In this work, we determine the effects of VP40 mutations altering electrostatics on PM interactions and subsequent budding. VP40 mutations that modify surface electrostatics affect viral assembly and budding by altering VP40 membrane-binding capabilities. Mutations that increase VP40 net positive charge by one (e.g., Gly to Arg or Asp to Ala) increase VP40 affinity for phosphatidylserine and phosphatidylinositol 4,5-bisphosphate in the host cell PM. This increased affinity enhances PM association and budding efficiency leading to more effective formation of virus-like particles. In contrast, mutations that decrease net positive charge by one (e.g., Gly to Asp) lead to a decrease in assembly and budding because of decreased interactions with the anionic PM. Taken together, our results highlight the sensitivity of slight electrostatic changes on the VP40 surface for assembly and budding. Understanding the effects of single amino acid substitutions on viral budding and assembly will be useful for explaining changes in the infectivity and virulence of different EBOV strains, VP40 variants that occur in nature, and for long-term drug discovery endeavors aimed at EBOV assembly and budding.
Language	English
Publishing date	2024-03-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.107213
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Article: The SARS-CoV-2 nucleoprotein associates with anionic lipid membranes.

Dutta, Mandira / Su, Yuan / Voth, Gregory A / Stahelin, Robert V

bioRxiv : the preprint server for biology

2023

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a lipid-enveloped virus that acquires its lipid bilayer from the host cell it infects. SARS-CoV-2 can spread from cell to cell or from patient to patient by undergoing assembly and budding ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a lipid-enveloped virus that acquires its lipid bilayer from the host cell it infects. SARS-CoV-2 can spread from cell to cell or from patient to patient by undergoing assembly and budding to form new virions. The assembly and budding of SARS-CoV-2 is mediated by several structural proteins known as envelope (E), membrane (M), nucleoprotein (N) and spike (S), which can form virus-like particles (VLPs) when co-expressed in mammalian cells. Assembly and budding of SARS-CoV-2 from the host ER-Golgi intermediate compartment is a critical step in the virus acquiring its lipid bilayer. To date, little information is available on how SARS-CoV-2 assembles and forms new viral particles from host membranes. In this study, we find the N protein can strongly associate with anionic lipids including phosphoinositides and phosphatidylserine. Moreover, lipid binding is shown to occur in the N protein C-terminal domain, which is supported by extensive
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.15.557899
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Article: Evaluation of Fendiline Treatment in VP40 System with Nucleation-Elongation Process: A Computational Model of Ebola Virus Matrix Protein Assembly.

Liu, Xiao / Husby, Monica / Stahelin, Robert V / Pienaar, Elsje

bioRxiv : the preprint server for biology

2023

Abstract: Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 (BSL-4) laboratories hinders experimental work to advance our understanding of EBOV and ... ...

Abstract	Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the 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.
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.03.551833
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Article ; Online: The Ebola virus matrix protein VP40 hijacks the host plasma membrane to form virus envelope.

Amiar, Souad / Stahelin, Robert V

Journal of lipid research

2020 Volume 61, Issue 7, Page(s) 971

MeSH term(s)	Cell Membrane/metabolism ; Cell Membrane/virology ; HEK293 Cells ; Host Microbial Interactions ; Humans ; Microscopy, Electron, Transmission ; Nucleoproteins/metabolism ; Viral Core Proteins/metabolism ; Viral Envelope/metabolism
Chemical Substances	Nucleoproteins ; Viral Core Proteins ; nucleoprotein VP40, Ebola virus
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Editorial
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.ILR120000753
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