Structural basis for Marburg virus VP35?mediated
immune evasion mechanisms
http://www.pnas.org/content/109/50/20661.full.pdf#page=1&view=FitH
Filoviruses, marburgvirus (MARV) and ebolavirus (EBOV), are causa-
tive agents of highly lethal hemorrhagic fever in humans. MARV
and EBOV share a common genome organization but show impor-
tant differences in replication complex formation, cell entry, host
tropism, transcriptional regulation, and immune evasion. Multifunc-
tional filoviral viral protein (VP) 35 proteins inhibit innate immune
responses. Recent studies suggest double-stranded (ds)RNA seques-
tration is a potential mechanism that allows EBOV VP35 to antago-
nize 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-de-
pendent RLR activation and interferon (IFN) regulatory factor 3
(IRF3) phosphorylation by IFN kinases TRAF family member-associ-
ated 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 associ-
ated 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 filo-
viral VP35 fold, as shown here, reveal the structural and functional
plasticity of a highly conserved virulence factor.
PNAS | December 11, 2012 | vol. 109 | no. 50 | 20661?20666
immune evasion mechanisms
http://www.pnas.org/content/109/50/20661.full.pdf#page=1&view=FitH
Filoviruses, marburgvirus (MARV) and ebolavirus (EBOV), are causa-
tive agents of highly lethal hemorrhagic fever in humans. MARV
and EBOV share a common genome organization but show impor-
tant differences in replication complex formation, cell entry, host
tropism, transcriptional regulation, and immune evasion. Multifunc-
tional filoviral viral protein (VP) 35 proteins inhibit innate immune
responses. Recent studies suggest double-stranded (ds)RNA seques-
tration is a potential mechanism that allows EBOV VP35 to antago-
nize 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-de-
pendent RLR activation and interferon (IFN) regulatory factor 3
(IRF3) phosphorylation by IFN kinases TRAF family member-associ-
ated 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 associ-
ated 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 filo-
viral VP35 fold, as shown here, reveal the structural and functional
plasticity of a highly conserved virulence factor.
PNAS | December 11, 2012 | vol. 109 | no. 50 | 20661?20666