4 years ago

Cooperation of the Ebola proteins VP40 and GP1,2 with BST2 to activate NF-κβ independently of virus-like particle trapping.

Rizk MG, Guatelli J, Basler CF
BST2 is a host protein with dual functions in response to viral infections: it traps newly assembled enveloped virions at the plasma membrane of infected cells, and it induces NF-κβ activity, especially in the context of retroviral assembly. In this study, we examined whether Ebola virus proteins affect BST2-mediated induction of NF-κβ. We found that the Ebola matrix protein, VP40, and envelope glycoprotein, GP, each cooperate with BST2 to induce NF-κβ activity, with maximal activity when all three proteins are expressed. Unlike the Human Immunodeficiency Virus type 1 Vpu protein, which antagonizes both virion-entrapment and the activation of NF-κβ by BST2, Ebola GP does not inhibit NF-κβ signaling even while it antagonizes the entrapment of virus-like particles. GP from Reston Ebola virus, a non-pathogenic species in humans, showed a similar phenotype to GP from Zaire Ebola, a highly pathogenic species, in terms of both the activation of NF-κβ and the antagonism of virion-entrapment. Although Ebola VP40 and GP both activate NF-κβ independently of BST2, VP40 is the more potent activator. Activation of NF-κβ by the Ebola proteins either alone or together with BST2 requires the canonical NF-κβ signaling pathway. Mechanistically, the maximal NF-κβ activation by GP, VP40, and BST2 together requires the ectodomain cysteines needed for BST2-dimerization, the putative BST2 tetramerization residue L70, and Y6 of a potential hemi-ITAM motif in BST2's cytoplasmic domain. BST2 with a GPI anchor signal-deletion, which is not expressed at the plasma membrane and is unable to entrap virions, activated NF-κβ in concert with the Ebola proteins at least as effectively as wild type BST2. Signaling by the GPI-anchor mutant also depended on Y6 of BST2. Overall, our data show that activation of NF-κβ by BST2 is independent of virion-entrapment in the case of Ebola virus. Nonetheless, BST2 may induce or amplify proinflammatory signaling during Ebola virus infection, potentially contributing to the dysregulated cytokine response that is a hallmark of Ebola virus disease.IMPORTANCE Understanding how the host responds to viral infections informs the development of therapeutics and vaccines. We asked how proinflammatory signaling by the host protein BST2/tetherin, which is mediated by the transcription factor NF-κβ, responds to Ebola proteins. Although the Ebola virus envelope glycoprotein (GP1,2) antagonizes the trapping of newly formed virions at the plasma membrane by BST2, we found that it does not inhibit BST2's ability to induce NF-κβ activity. This distinguishes GP1,2 from the HIV-1 protein Vpu, the prototype BST2-antagonist, which inhibits both virion-entrapment and the induction of NF-κβ activity. Ebola GP1,2, the Ebola matrix protein VP40, and BST2 are at least additive with respect to the induction of NF-κβ activity. The effects of these proteins converge on an intracellular signaling pathway that depends on a protein-modification termed neddylation. Better mechanistic understanding of these phenomena could provide targets for therapies that modulate the inflammatory response during Ebola virus disease.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28878074

DOI: PubMed:28878074

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.