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Title: VP24-Karyopherin Alpha Binding Affinities Differ between Ebolavirus Species, Influencing Interferon Inhibition and VP24 Stability

Journal Article · · Journal of Virology
DOI:https://doi.org/10.1128/JVI.01715-16· OSTI ID:1351400
 [1];  [2];  [1];  [2];  [2];  [2];  [3];  [4]
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  2. Washington Univ. School of Medicine in St. Louis, St. Louis, MO (United States)
  3. Icahn School of Medicine at Mount Sinai, New York, NY (United States); Georgia State Univ., Atlanta, GA (United States)
  4. Wake Forest Univ., Winston-Salem, NC (United States)
+ Show Author Affiliations

Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Reston ebolavirus (RESTV) belong to the same genus but exhibit different virulence properties. VP24 protein, a structural protein present in all family members, blocks interferon (IFN) signaling and likely contributes to virulence. Inhibition of IFN signaling by EBOV VP24 (eVP24) involves its interaction with the NPI-1 subfamily of karyopherin alpha (KPNA) nuclear transporters. Here, we evaluated eVP24, BDBV VP24 (bVP24), and RESTV VP24 (rVP24) interactions with three NPI-1 subfamily KPNAs (KPNA1, KPNA5, and KPNA6). Using purified proteins, we demonstrated that each VP24 binds to each of the three NPI-1 KPNAs. bVP24, however, exhibited approximately 10-fold-lower KPNA binding affinity than either eVP24 or rVP24. Cell-based assays also indicate that bVP24 exhibits decreased KPNA interaction, decreased suppression of IFN induced gene expression, and a decreased half-life in transfected cells compared to eVP24 or rVP24. Amino acid sequence alignments between bVP24 and eVP24 also identified residues within and surrounding the previously defined eVP24-KPNA5 binding interface that decrease eVP24-KPNA affinity or bVP24-KPNA affinity. VP24 mutations that lead to reduced KPNA binding affinity also decrease IFN inhibition and shorten VP24 half-lives. Here, these data identify novel functional differences in VP24-KPNA interaction and reveal a novel impact of the VP24-KPNA interaction on VP24 stability. The interaction of Ebola virus (EBOV) VP24 protein with host karyopherin alpha (KPNA) proteins blocks type I interferon (IFN) signaling, which is a central component of the host innate immune response to viral infection. Here, we quantitatively compared the interactions of VP24 proteins from EBOV and two members of the Ebolavirus genus, Bundibugyo virus (BDBV) and Reston virus (RESTV). The data reveal lower binding affinity of the BDBV VP24 (bVP24) for KPNAs and demonstrate that the interaction with KPNA modulates inhibition of IFN signaling and VP24 stability. The effect of KPNA interaction on VP24 stability is a novel functional consequence of this virus-host interaction, and the differences identified between viral species may contribute to differences in pathogenesis.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Institutes of Health (NIH)
Grant/Contract Number:
AI109945; AI120943; AI007647
OSTI ID:
1351400
Journal Information:
Journal of Virology, Vol. 91, Issue 4; ISSN 0022-538X
Publisher:
American Society for MicrobiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 11 works
Citation information provided by
Web of Science

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Cited By (7)

Filovirus Strategies to Escape Antiviral Responses book January 2017
Treatment-focused Ebola trials, supportive care and future of filovirus care journal December 2017
Is the Bombali virus pathogenic in humans? journal April 2019
Regulation of the Ebola Virus VP24 Protein by SUMO journal October 2019
Importin α1 is required for nuclear import of herpes simplex virus proteins and capsid assembly in fibroblasts and neurons journal January 2018
Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism journal December 2017
Development and Validation of a Novel Dual Luciferase Reporter Gene Assay to Quantify Ebola Virus VP24 Inhibition of IFN Signaling journal February 2018

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Related Subjects

60 APPLIED LIFE SCIENCES
STAT1
Ebola virus
filovirus
interferons
karyopherin
protein stability