Abstract
RIG-I is a pattern recognition receptor that senses viral RNA and is crucial for host innate immune defense. Here, we describe a mechanism of RIG-I activation through amidotransferase-mediated deamidation. We show that viral homologs of phosphoribosylformylglycinamidine synthetase (PFAS), although lacking intrinsic enzyme activity, recruit cellular PFAS to deamidate and activate RIG-I. Accordingly, depletion and biochemical inhibition of PFAS impair RIG-I deamidation and concomitant activation. Purified PFAS and viral homolog thereof deamidate RIG-I in vitro. Ultimately, herpesvirus hijacks activated RIG-I to avoid antiviral cytokine production; loss of RIG-I or inhibition of RIG-I deamidation results in elevated cytokine production. Together, these findings demonstrate a surprising mechanism of RIG-I activation that is mediated by an enzyme.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / metabolism
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Animals
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Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / genetics
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Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / immunology*
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Cell Line
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Cytokines / antagonists & inhibitors
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Cytokines / biosynthesis
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DEAD Box Protein 58
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DEAD-box RNA Helicases / antagonists & inhibitors
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / immunology*
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DEAD-box RNA Helicases / metabolism
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Enzyme Activation
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Fibroblasts / enzymology
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Fibroblasts / immunology
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Fibroblasts / virology
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Gammaherpesvirinae / genetics
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Gammaherpesvirinae / immunology*
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Gene Expression Regulation
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HEK293 Cells
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Humans
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Immune Evasion / genetics*
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Immunity, Innate
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Mice
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Molecular Mimicry
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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RNA, Viral / genetics
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RNA, Viral / immunology*
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Receptors, Immunologic
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Signal Transduction
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Viral Proteins / genetics
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Viral Proteins / immunology*
Substances
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Amides
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Cytokines
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RNA, Small Interfering
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RNA, Viral
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Receptors, Immunologic
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Viral Proteins
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RIGI protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
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phosphoribosylformylglycinamidine synthetase