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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| Published in: | Cell host & microbe Vol. 14; no. 1; p. 74 |
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| Main Authors: | , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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17.07.2013
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| ISSN: | 1934-6069, 1934-6069 |
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Ebihara, Hideki Amarasinghe, Gaya K Mire, Chad E Yen, Benjamin Geisbert, Thomas W Liu, Gai Basler, Christopher F Luthra, Priya Ramanan, Parameshwaran Tsuda, Yoshimi Weisend, Carla Leung, Daisy W |
| Author_xml | – sequence: 1 givenname: Priya surname: Luthra fullname: Luthra, Priya organization: Department of Microbiology, Icahn School of Medicine at Mount Sinai School, New York, NY 10029, USA – sequence: 2 givenname: Parameshwaran surname: Ramanan fullname: Ramanan, Parameshwaran – sequence: 3 givenname: Chad E surname: Mire fullname: Mire, Chad E – sequence: 4 givenname: Carla surname: Weisend fullname: Weisend, Carla – sequence: 5 givenname: Yoshimi surname: Tsuda fullname: Tsuda, Yoshimi – sequence: 6 givenname: Benjamin surname: Yen fullname: Yen, Benjamin – sequence: 7 givenname: Gai surname: Liu fullname: Liu, Gai – sequence: 8 givenname: Daisy W surname: Leung fullname: Leung, Daisy W – sequence: 9 givenname: Thomas W surname: Geisbert fullname: Geisbert, Thomas W – sequence: 10 givenname: Hideki surname: Ebihara fullname: Ebihara, Hideki – sequence: 11 givenname: Gaya K surname: Amarasinghe fullname: Amarasinghe, Gaya K – sequence: 12 givenname: Christopher F surname: Basler fullname: Basler, Christopher F |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23870315$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome |
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