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Title: Structural basis for Marburg virus VP35-mediated immune evasion mechanisms

Abstract

Filoviruses, marburgvirus (MARV) and ebolavirus (EBOV), are causative agents of highly lethal hemorrhagic fever in humans. MARV and EBOV share a common genome organization but show important differences in replication complex formation, cell entry, host tropism, transcriptional regulation, and immune evasion. Multifunctional filoviral viral protein (VP) 35 proteins inhibit innate immune responses. Recent studies suggest double-stranded (ds)RNA sequestration is a potential mechanism that allows EBOV VP35 to antagonize retinoic-acid inducible gene-I (RIG-I) like receptors (RLRs) that are activated by viral pathogen–associated molecular patterns (PAMPs), such as double-strandedness and dsRNA blunt ends. Here, we show that MARV VP35 can inhibit IFN production at multiple steps in the signaling pathways downstream of RLRs. The crystal structure of MARV VP35 IID in complex with 18-bp dsRNA reveals that despite the similar protein fold as EBOV VP35 IID, MARV VP35 IID interacts with the dsRNA backbone and not with blunt ends. Functional studies show that MARV VP35 can inhibit dsRNA-dependent RLR activation and interferon (IFN) regulatory factor 3 (IRF3) phosphorylation by IFN kinases TRAF family member-associated NFkb activator (TANK) binding kinase-1 (TBK-1) and IFN kB kinase e (IKKe) in cell-based studies. We also show that MARV VP35 can only inhibit RIG-I and melanoma differentiationmore » associated gene 5 (MDA5) activation by double strandedness of RNA PAMPs (coating backbone) but is unable to inhibit activation of RLRs by dsRNA blunt ends (end capping). In contrast, EBOV VP35 can inhibit activation by both PAMPs. Insights on differential PAMP recognition and inhibition of IFN induction by a similar filoviral VP35 fold, as shown here, reveal the structural and functional plasticity of a highly conserved virulence factor.« less

Authors:
; ; ; ; ; ; ; ; ; ;  [1]
  1. Sinai
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1084115
Resource Type:
Journal Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 109; Journal Issue: (50) ; 12, 2012; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Ramanan, Parameshwaran, Edwards, Megan R., Shabman, Reed S., Leung, Daisy W., Endlich-Frazier, Ariel C., Borek, Dominika M., Otwinowski, Zbyszek, Liu, Gai, Huh, Juyoung, Basler, Christopher F., Amarasinghe, Gaya K., WU-MED), and UTSMC). Structural basis for Marburg virus VP35-mediated immune evasion mechanisms. United States: N. p., 2013. Web. doi:10.1073/pnas.1213559109.
Ramanan, Parameshwaran, Edwards, Megan R., Shabman, Reed S., Leung, Daisy W., Endlich-Frazier, Ariel C., Borek, Dominika M., Otwinowski, Zbyszek, Liu, Gai, Huh, Juyoung, Basler, Christopher F., Amarasinghe, Gaya K., WU-MED), & UTSMC). Structural basis for Marburg virus VP35-mediated immune evasion mechanisms. United States. doi:10.1073/pnas.1213559109.
Ramanan, Parameshwaran, Edwards, Megan R., Shabman, Reed S., Leung, Daisy W., Endlich-Frazier, Ariel C., Borek, Dominika M., Otwinowski, Zbyszek, Liu, Gai, Huh, Juyoung, Basler, Christopher F., Amarasinghe, Gaya K., WU-MED), and UTSMC). Mon . "Structural basis for Marburg virus VP35-mediated immune evasion mechanisms". United States. doi:10.1073/pnas.1213559109.
@article{osti_1084115,
title = {Structural basis for Marburg virus VP35-mediated immune evasion mechanisms},
author = {Ramanan, Parameshwaran and Edwards, Megan R. and Shabman, Reed S. and Leung, Daisy W. and Endlich-Frazier, Ariel C. and Borek, Dominika M. and Otwinowski, Zbyszek and Liu, Gai and Huh, Juyoung and Basler, Christopher F. and Amarasinghe, Gaya K. and WU-MED) and UTSMC)},
abstractNote = {Filoviruses, marburgvirus (MARV) and ebolavirus (EBOV), are causative agents of highly lethal hemorrhagic fever in humans. MARV and EBOV share a common genome organization but show important differences in replication complex formation, cell entry, host tropism, transcriptional regulation, and immune evasion. Multifunctional filoviral viral protein (VP) 35 proteins inhibit innate immune responses. Recent studies suggest double-stranded (ds)RNA sequestration is a potential mechanism that allows EBOV VP35 to antagonize retinoic-acid inducible gene-I (RIG-I) like receptors (RLRs) that are activated by viral pathogen–associated molecular patterns (PAMPs), such as double-strandedness and dsRNA blunt ends. Here, we show that MARV VP35 can inhibit IFN production at multiple steps in the signaling pathways downstream of RLRs. The crystal structure of MARV VP35 IID in complex with 18-bp dsRNA reveals that despite the similar protein fold as EBOV VP35 IID, MARV VP35 IID interacts with the dsRNA backbone and not with blunt ends. Functional studies show that MARV VP35 can inhibit dsRNA-dependent RLR activation and interferon (IFN) regulatory factor 3 (IRF3) phosphorylation by IFN kinases TRAF family member-associated NFkb activator (TANK) binding kinase-1 (TBK-1) and IFN kB kinase e (IKKe) in cell-based studies. We also show that MARV VP35 can only inhibit RIG-I and melanoma differentiation associated gene 5 (MDA5) activation by double strandedness of RNA PAMPs (coating backbone) but is unable to inhibit activation of RLRs by dsRNA blunt ends (end capping). In contrast, EBOV VP35 can inhibit activation by both PAMPs. Insights on differential PAMP recognition and inhibition of IFN induction by a similar filoviral VP35 fold, as shown here, reveal the structural and functional plasticity of a highly conserved virulence factor.},
doi = {10.1073/pnas.1213559109},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = (50) ; 12, 2012,
volume = 109,
place = {United States},
year = {2013},
month = {7}
}