Ebola viral protein 24

Last updated
eVP24
Identifiers
SymboleVP24
Pfam PF06389
InterPro IPR009433
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Ebola viral protein 24 (eVP24) is considered a multifunctional secondary matrix protein present in viral particles. [1] The broad roles eVP24 performs involve the formation of fully functional and infectious viral particles, promotion of filamentous nucleocapsid formation, mediation of host responses to infection, and suppression of the host innate immune system. It has been noted that eVP24 function can overlap with that of two other viral proteins; eVP40 matrix protein which functions in virus budding, and eVP35 which is also associated with immune suppression. [2] [3]

Contents

History

Research

The first recorded human outbreak of Ebola virus disease was in 1976 and since then, there has been considerable effort to define the progression of the disease and the virus responsible. [4] The history of Ebola virus characterization is rather short as most research on the mechanisms employed by the virus have occurred in the last two decades. This is due to the intensive biohazard containment required for laboratory studies of the virus and the difficulty in obtaining samples for study, particularly in common outbreak regions. The isolation of viral cDNAs has allowed research into viral gene products to progress. [5] The genome of the Ebola virus was found to encode seven proteins: glycoprotein; nucleoprotein; matrix proteins, VP40 and VP24; nonstructural proteins, VP30 and VP35; and viral polymerase. The functions of the viral proteins remained the last to be well investigated. In particular, eVP24 remained the least studied for some time. [2]

Characterization

eVP24 was initially described as a matrix protein that had similar properties and functions of eVP40. eVP24 was found to have characteristics of typical viral matrix proteins, such as a strong association with lipid bilayers and the ability to oligomerize to form tetramers. Like eVP40, eVP24 was found to be essential in virion assembly and budding. Later research indicated that the expression of eVP24 was required to switch from viral transcription and replication to virion assembly. [1] A new role for eVP24 was found when its expression was monitored in rodent species where changes in eVP24 seemed to be responsible for enhancing virulence, indicating that adaption of Ebola in animal models occurs through mutations in eVP24. [1] Additionally, eVP24 inhibits interferon signaling by competitively binding to karyopherins which blocks phosphorylated STAT1 nuclear import. In 2014, it was found that this mechanism interferes with the cells response to viral infection, which suppressed the innate immune response, allowing the virus to proliferate in the body. [6]

Function

eVP24 disrupts the signaling pathway of STAT1. The STAT1 protein is phosphorylated by interferons in response to viral infection causing it to express a non-classical nuclear localization signal and bind to the importin protein karyopherin-α (KPNA). Once bound to KPNA, STAT1 is transported to the nucleus where it stimulates gene transcription in response to viral infection. [6] Classical nuclear localization signals are bound by arms 2-4 or by 6-8 of KPNA while non-classical nuclear localization signals are bound by KPNA 1, 5 and 6 in arms 8-10 allowing non classical signals to be transported at the same time as classical signals, providing faster signaling of certain signals. [6] The eVP24 protein operates by binding to KPNA preventing the binding of STAT1. As a result, STAT1 is not able to elicit an immune response, however nuclear import is able to proceed as normal which may be important for viral replication. This means that eVP24 prevents the activation of an immune response against the Ebola virus without sacrificing its ability to have viral components transported to the nucleus or the target cell. [6] eVP24 provides Ebola with an advantages over other viruses which disrupt STAT1 because unlike most other viruses, eVP24 uses mimicry of the STAT1 protein. This makes it very unlikely for the host to develop an adaptation as mutations in KPNA which prevent eVP24 binding are also likely to prevent STAT1 signalling. [6]

Mechanism

eVP24 prevents the function of KPNA by binding in a region which overlaps with the binding region of STAT1. This is accomplished by the high binding affinity between KNPA and eVP24. [3] These proteins have very high complementarity in the binding interface, similar to the complementarity shown between antibodies and antigens. In addition, the binding interface is large; over 2000 angstroms squared of solvent accessible surface is buried by the binding. Overall binding takes place with very little conformational change in either protein. [3] There are three clusters of residues on eVP24 which form contacts to KPNA. These are located at residue positions 115 to 140, 184 to 186, and 201 to 207. Mutation of any single residue does not significantly reduce the binding of eVP24 to KPNA which demonstrates the robust mechanism of the viral protein. [3] KPNA proteins have 10 armadillo repeats each consisting of three alpha helices which determine their binding specificity, the second helix from ARM 9 and 10 form a hydrophobic core with helix 6 of eVP24 adding to the stability of the complex. [3] The binding sites for eVP24 and STAT1 have been shown to overlap. Mutation in any one of four residues in KPNA at positions 434, 474, 477 or 484 prevent binding to STAT1. Similarly, the mutations in residues 474, 477 or 484 of KPNA reduce the binding of eVP24. Additionally and critically, the binding of eVP24 does not prevent the binding of cargo proteins with classical nuclear localization signals as, like STAT1, eVP24 causes very little conformational changes in KPNA. [3]

Effects on symptom progression

eVP24 acts as an antagonist to PY-STAT1 on KPNA. With eVP24 being transported to the nucleus instead of STAT1, the interferon-stimulated genes IFN-α/IFN-β and IFN-γ are disrupted and the cell does not enter an antiviral state. [6] STAT1 has been shown to regulate the expression of certain immunoglobulins. More specifically, class switching from the predominant IgM to IgG2a was not present in STAT1-deficient cells. IgG2a plays a critical role in protection against pathogens and therefore without it, the cell is more susceptible to said pathogen. [7] STAT1 has also been shown to regulate cell death by the inhibition of anti-apoptotic proteins Bcl-2 and Bcl-xL. [8] STAT1 also induces the expression of procaspases, which are important factors in apoptosis signaling. [9] When nuclear transport of STAT1 is inhibited pro-apoptotic signalling is disrupted, leading to decreased cell death.

Current and future research

The evasion of the host cell immune system is key in to the rapid replication and dispersion through the body by the Ebola virus. Current research is exploring how eVP24 enables this phenomenon to occur. The discovery of STAT1 nuclear import disruption by eVP24 binding to KPNA has already provided scientists with one mechanism for the inhibition of the immune response in the cell. Other current Ebola research is focused on developing treatments or vaccines against the virus. Early investigations into potential vaccines showed that in mice models, the highest levels of protection occurred after vaccination with viral-like particles expressing eVP24. [10] However, at that time the role of eVP24 was still largely unknown. In the wake of the 2014 Ebola outbreak in West Africa, the largest and deadliest outbreak to date, there has been a considerable increase in research focused on developing a vaccine for Ebola.

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<i>Henipavirus</i> Genus of RNA viruses

Henipavirus is a genus of negative-strand RNA viruses in the family Paramyxoviridae, order Mononegavirales containing six established species, and numerous others still under study. Henipaviruses are naturally harboured by several species of small mammals, notably pteropid fruit bats, microbats of several species, and shrews. Henipaviruses are characterised by long genomes and a wide host range. Their recent emergence as zoonotic pathogens capable of causing illness and death in domestic animals and humans is a cause of concern.

<i>Indiana vesiculovirus</i> Species of virus

Indiana vesiculovirus, formerly Vesicular stomatitis Indiana virus is a virus in the family Rhabdoviridae; the well-known Rabies lyssavirus belongs to the same family. VSIV can infect insects, cattle, horses and pigs. It has particular importance to farmers in certain regions of the world where it infects cattle. This is because its clinical presentation is identical to the very important foot and mouth disease virus.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.

<span class="mw-page-title-main">Viral envelope</span> Outermost layer of many types of the infectious agent

A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. A viral envelope protein or E protein is a protein in the envelope, which may be acquired by the capsid from an infected host cell.

<span class="mw-page-title-main">Interferon-alpha/beta receptor</span> Heterodimeric receptor

The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ.

<span class="mw-page-title-main">STAT1</span> Transcription factor and coding gene in humans

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.

<span class="mw-page-title-main">Antibody-dependent enhancement</span> Antibodies rarely making an infection worse instead of better

Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to respiratory disease. It has been observed in HIV, RSV virus and Dengue virus and is monitored for in vaccine development.

<span class="mw-page-title-main">STAT2</span> Protein-coding gene in Homo sapiens

Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). STAT2 sequence identity between mouse and human is only 68%.

<span class="mw-page-title-main">Importin subunit alpha-1</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-1 is a protein that in humans is encoded by the KPNA2 gene.

<span class="mw-page-title-main">Importin subunit alpha-7</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-7 is a protein that in humans is encoded by the KPNA6 gene.

<span class="mw-page-title-main">Importin subunit alpha-3</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-3, also known as karyopherin subunit alpha-4, is a protein that in humans is encoded by the KPNA4 gene.

<span class="mw-page-title-main">Importin subunit alpha-6</span> Protein-coding gene in the species Homo sapiens

Importin subunit alpha-6 is a protein that in humans is encoded by the KPNA5 gene.

<span class="mw-page-title-main">Tetherin</span> Mammalian protein found in Homo sapiens

Tetherin, also known as bone marrow stromal antigen 2, is a lipid raft associated protein that in humans is encoded by the BST2 gene. In addition, tetherin has been designated as CD317. This protein is constitutively expressed in mature B cells, plasma cells and plasmacytoid dendritic cells, and in many other cells, it is only expressed as a response to stimuli from IFN pathway.

Importin alpha, or karyopherin alpha refers to a class of adaptor proteins that are involved in the import of proteins into the cell nucleus. They are a sub-family of karyopherin proteins.

<i>Zaire ebolavirus</i> Species of virus affecting humans and animals

Zaire ebolavirus, more commonly known as Ebola virus, is one of six known species within the genus Ebolavirus. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal hemorrhagic fever in humans and other mammals, known as Ebola virus disease (EVD). Ebola virus has caused the majority of human deaths from EVD, and was the cause of the 2013–2016 epidemic in western Africa, which resulted in at least 28,646 suspected cases and 11,323 confirmed deaths.

The cGAS–STING pathway is a component of the innate immune system that functions to detect the presence of cytosolic DNA and, in response, trigger expression of inflammatory genes that can lead to senescence or to the activation of defense mechanisms. DNA is normally found in the nucleus of the cell. Localization of DNA to the cytosol is associated with tumorigenesis, viral infection, and invasion by some intracellular bacteria. The cGAS – STING pathway acts to detect cytosolic DNA and induce an immune response.

ORF6 is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is not present in MERS-CoV. It is thought to reduce the immune system response to viral infection through interferon antagonism.

Endothelial cell tropism or endotheliotropism is a type of tissue tropism or host tropism that characterizes an pathogen's ability to recognize and infect an endothelial cell. Pathogens, such as viruses, can target a specific tissue type or multiple tissue types. Like other cells, the endothelial cell possesses several features that supports a productive viral infection a cell including, cell surface receptors, immune responses, and other virulence factors. Endothelial cells are found in various tissue types such as in the capillaries, veins, and arteries in the human body. As endothelial cells line these blood vessels and critical networks that extend access to various human organ systems, the virus entry into these cells can be detrimental to virus spread across the host system and affect clinical course of disease. Understanding the mechanisms of how viruses attach, enter, and control endothelial functions and host responses inform infectious disease understanding and medical countermeasures.

References

  1. 1 2 3 Shabman RS, Gulcicek EE, Stone KL, Basler CF (November 2011). "The Ebola virus VP24 protein prevents hnRNP C1/C2 binding to karyopherin α1 and partially alters its nuclear import". The Journal of Infectious Diseases. 204 Suppl 3: S904-10. doi:10.1093/infdis/jir323. PMC   3189985 . PMID   21987768.
  2. 1 2 Han Z, Boshra H, Sunyer JO, Zwiers SH, Paragas J, Harty RN (February 2003). "Biochemical and functional characterization of the Ebola virus VP24 protein: implications for a role in virus assembly and budding". Journal of Virology. 77 (3): 1793–800. doi:10.1128/JVI.77.3.1793-1800.2003. PMC   140957 . PMID   12525613.
  3. 1 2 3 4 5 6 Xu W, Edwards MR, Borek DM, Feagins AR, Mittal A, Alinger JB, et al. (August 2014). "Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1". Cell Host & Microbe. 16 (2): 187–200. doi:10.1016/j.chom.2014.07.008. PMC   4188415 . PMID   25121748.
  4. ↑ Pourrut X, Kumulungui B, Wittmann T, Moussavou G, Délicat A, Yaba P, Nkoghe D, Gonzalez JP, Leroy EM (June 2005). "The natural history of Ebola virus in Africa". Microbes and Infection. 7 (7–8): 1005–14. doi: 10.1016/j.micinf.2005.04.006 . PMID   16002313.
  5. ↑ Sullivan N, Yang ZY, Nabel GJ (September 2003). "Ebola virus pathogenesis: implications for vaccines and therapies". Journal of Virology. 77 (18): 9733–7. doi:10.1128/JVI.77.18.9733-9737.2003. PMC   224575 . PMID   12941881.
  6. 1 2 3 4 5 6 Daugherty MD, Malik HS (August 2014). "How a virus blocks a cellular emergency access lane to the nucleus, STAT!". Cell Host & Microbe. 16 (2): 150–152. doi: 10.1016/j.chom.2014.07.013 . PMID   25121743.
  7. ↑ Yoshimoto T, Okada K, Morishima N, Kamiya S, Owaki T, Asakawa M, Iwakura Y, Fukai F, Mizuguchi J (August 2004). "Induction of IgG2a class switching in B cells by IL-27". Journal of Immunology. 173 (4): 2479–85. doi: 10.4049/jimmunol.173.4.2479 . PMID   15294962.
  8. ↑ Stephanou A, Brar BK, Knight RA, Latchman DS (March 2000). "Opposing actions of STAT-1 and STAT-3 on the Bcl-2 and Bcl-x promoters". Cell Death and Differentiation. 7 (3): 329–30. doi: 10.1038/sj.cdd.4400656 . PMID   10866494.
  9. ↑ Lee CK, Smith E, Gimeno R, Gertner R, Levy DE (February 2000). "STAT1 affects lymphocyte survival and proliferation partially independent of its role downstream of IFN-gamma". Journal of Immunology. 164 (3): 1286–92. doi: 10.4049/jimmunol.164.3.1286 . PMID   10640742.
  10. ↑ Wilson JA, Bray M, Bakken R, Hart MK (August 2001). "Vaccine potential of Ebola virus VP24, VP30, VP35, and VP40 proteins". Virology. 286 (2): 384–90. doi: 10.1006/viro.2001.1012 . PMID   11485406.
This article incorporates text from the public domain Pfam and InterPro: IPR008986
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.