Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome

The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode pr...

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Bibliographic Details
Published in:	Cell host & microbe Vol. 14; no. 1; p. 74
Main Authors:	Luthra, Priya, Ramanan, Parameshwaran, Mire, Chad E, Weisend, Carla, Tsuda, Yoshimi, Yen, Benjamin, Liu, Gai, Leung, Daisy W, Geisbert, Thomas W, Ebihara, Hideki, Amarasinghe, Gaya K, Basler, Christopher F
Format:	Journal Article
Language:	English
Published:	United States 17.07.2013
Subjects:	Amino Acid Motifs Cell Line DEAD Box Protein 58 DEAD-box RNA Helicases - antagonists & inhibitors DEAD-box RNA Helicases - genetics DEAD-box RNA Helicases - metabolism Ebolavirus - chemistry Ebolavirus - genetics Ebolavirus - metabolism Hemorrhagic Fever, Ebola - enzymology Hemorrhagic Fever, Ebola - genetics Hemorrhagic Fever, Ebola - metabolism Hemorrhagic Fever, Ebola - virology Humans Protein Binding Receptors, Immunologic RNA, Viral - genetics RNA, Viral - metabolism RNA-Binding Proteins - antagonists & inhibitors RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Viral Regulatory and Accessory Proteins - antagonists & inhibitors Viral Regulatory and Accessory Proteins - chemistry Viral Regulatory and Accessory Proteins - genetics Viral Regulatory and Accessory Proteins - metabolism
ISSN:	1934-6069, 1934-6069
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Summary:	The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1934-6069 1934-6069
DOI:	10.1016/j.chom.2013.06.010