The Minor Matrix Protein VP24 from Ebola Virus Lacks Direct Lipid-Binding Properties

Su, Yu‐Nung; Stahelin, Robert V.

doi:10.3390/v12080869

Cited by 2 publications

(2 citation statements)

References 45 publications

(79 reference statements)

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“…VP24 is also known as the minor viral matrix protein as it can be associated with cellular membranes [ 23 ]. However, a recent publication observed that EBOV VP24 does not associate with lipids, so its presence on the viral matrix layer likely does not depend on direct lipid interactions [ 68 ].…”

Section: Ebola Virus: From a Virology Point Of Viewmentioning

confidence: 99%

Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

Almeida-Pinto,

Pinto,

Rocha

2024

Infect Dis Ther

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In 1976 Ebola revealed itself to the world, marking the beginning of a series of localized outbreaks. However, it was the Ebola outbreak that began in 2013 that incited fear and anxiety around the globe. Since then, our comprehension of the virus has been steadily expanding. Ebola virus (EBOV), belonging to the Orthoebolavirus genus of the Filoviridae family, possesses a non-segmented, negative single-stranded RNA genome comprising seven genes that encode multiple proteins. These proteins collectively orchestrate the intricate process of infecting host cells. It is not possible to view each protein as monofunctional. Instead, they synergistically contribute to the pathogenicity of the virus. Understanding this multifaceted replication cycle is crucial for the development of effective antiviral strategies. Currently, two antibody-based therapeutics have received approval for treating Ebola virus disease (EVD). In 2022, the first evidence-based clinical practice guideline dedicated to specific therapies for EVD was published. Although notable progress has been made in recent years, deaths still occur. Consequently, there is an urgent need to enhance the therapeutic options available to improve the outcomes of the disease. Emerging therapeutics can target viral proteins as direct-acting antivirals or host factors as host-directed antivirals. They both have advantages and disadvantages. One way to bypass some disadvantages is to repurpose already approved drugs for non-EVD indications to treat EVD. This review offers detailed insight into the role of each viral protein in the replication cycle of the virus, as understanding how the virus interacts with host cells is critical to understanding how emerging therapeutics exert their activity. Using this knowledge, this review delves into the intricate mechanisms of action of current and emerging therapeutics.

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Section: Ebola Virus: From a Virology Point Of Viewmentioning

confidence: 99%

Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

Almeida-Pinto,

Pinto,

Rocha

2024

Infect Dis Ther

View full text Add to dashboard Cite

show abstract

“…VP24 was originally described as a minor matrix protein based on its presence in viral particles and the apparent capacity of VP24 from EBOV or MARV to associate with cellular membranes [7][8][9]. However, VP24 lacks measurable capacity to directly bind lipids [10]. Rather, VP24 interacts with NP and VP35 to promote formation of nucleocapsid-like structures (NCLS) nearly identical to the mature nucleocapsids found in virions [11].…”

Section: Introductionmentioning

confidence: 99%

The Role of Ebola Virus VP24 Nuclear Trafficking Signals in Infectious Particle Production

Vogel,

Nafziger,

Sharma

et al. 2024

Preprint

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Ebola virus (EBOV) protein VP24 carries out at least two critical functions. It promotes condensation of viral nucleocapsids, which is crucial for infectious virus production, and it suppresses interferon (IFN) signaling, which requires interaction with the NPI-1 subfamily of importin-α (IMPA) nuclear transport proteins. Interestingly, over-expressed IMPA leads to VP24 nuclear accumulation and a carboxy-terminus nuclear export signal (NES) has been reported, suggesting that VP24 may undergo nuclear trafficking. For the first time, we demonstrate that NPI-1 IMPA overexpression leads to the nuclear accumulation of VP24 during EBOV infection. To assess the functional impact of nuclear trafficking, we generated tetracistronic minigenomes encoding VP24 nuclear import and/or export signal mutants. The minigenomes, which also encodeRenillaluciferase and viral proteins VP40 and GP, were used to generate transcription and replication competent virus-like particles (trVLPs) that can be used to assess EBOV RNA synthesis, gene expression, entry and viral particle production. With this system, we confirmed that NES or IMPA binding site mutations altered VP24 nuclear localization, demonstrating functional trafficking signals. While these mutations minimally affected transcription and replication, the trVLPs exhibited impaired infectivity and formation of shortened nucleocapsids for the IMPA binding mutant. For the NES mutants, infectivity was reduced approximately 1000-fold. The NES mutant could still suppress IFN signaling but failed to promote nucleocapsid formation. To determine whether VP24 nuclear export is required for infectivity, the residues surrounding the wildtype NES were mutated to alanine or the VP24 NES was replaced with the Protein Kinase A Inhibitor NES. While nuclear export remained intact for these mutants, infectivity was severely impaired. These data demonstrate that VP24 undergoes nuclear trafficking and illuminates a separate and critical role for the NES and surrounding sequences in infectivity and nucleocapsid assembly.Author StatementEbola virus (EBOV) viral protein 24 (VP24) interacts with importin-α (IMPA) nuclear transport proteins to inhibit interferon signaling. VP24 also contains a nuclear export signal (NES). The capacity to bind IMPA and the presence of a NES suggest that VP24 traffics to the nucleus. However, this had not been demonstrated in the context of EBOV replication. In addition, whether these signals influence virus replication beyond effects on interferon responses has been unclear. Here, we demonstrate that VP24 traffics to the nucleus via IMPA during EBOV infection and in the context of an EBOV transcription and replication competent virus-like particle (trVLP) assay. Using the trVLP system, we also confirmed that VP24 possesses a functional nuclear export signal (NES). Mutations disrupting VP24-IMPA interaction or nuclear export reduced or abrogated trVLP infectivity, respectively. VP24 is known to be necessary for viral nucleocapsid maturation. The VP24 IMPA interface mutants yielded shortened nucleocapsids while VP24 NES mutations led to loss of nucleocapsid formation. Interestingly, VP24 mutants with intact NES function but altered sequences near the NES remain incapable of producing nucleocapsids. Together, these data demonstrate VP24 undergoes nuclear trafficking and reveals additional roles for both the IMPA interaction interface and the NES in nucleocapsid assembly.

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The Minor Matrix Protein VP24 from Ebola Virus Lacks Direct Lipid-Binding Properties

Cited by 2 publications

References 45 publications

Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

Navigating the Complex Landscape of Ebola Infection Treatment: A Review of Emerging Pharmacological Approaches

The Role of Ebola Virus VP24 Nuclear Trafficking Signals in Infectious Particle Production

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