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

Abstract

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.

• Authors: Priya Luthra, Parameshwaran Ramanan, Chad E Mire, Carla Weisend, Yoshimi Tsuda, Benjamin Yen, Gai Liu, Daisy W Leung, Thomas W Geisbert, Hideki Ebihara, Gaya K Amarasinghe, Christopher F Basler
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 14 Issue 1 Pg. 74-84 (Jul 17 2013) ISSN: 1934-6069 [Electronic] United States
• PMID: 23870315 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• PRKRA protein, human
• RNA, Viral
• RNA-Binding Proteins
• Receptors, Immunologic
• VP35 protein, filovirus
• Viral Regulatory and Accessory Proteins
• DDX58 protein, human
• DEAD Box Protein 58
• DEAD-box RNA Helicases

Topics

• Amino Acid Motifs
• Cell Line
• DEAD Box Protein 58
• DEAD-box RNA Helicases (antagonists & inhibitors, genetics, metabolism)
• Ebolavirus (chemistry, genetics, metabolism)
• Hemorrhagic Fever, Ebola (enzymology, genetics, metabolism, virology)
• Humans
• Protein Binding
• RNA, Viral (genetics, metabolism)
• RNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Receptors, Immunologic
• Viral Regulatory and Accessory Proteins (antagonists & inhibitors, chemistry, genetics, metabolism)