Abstract
Innate immunity to viruses involves receptors such as Retinoic Acid Induced Gene-1 (RIG-I), which senses viral RNA and triggers a signaling pathway involving the outer mitochondrial membrane protein mitochondrial antiviral signaling (MAVS). Recent work has identified that NLRX1, a member of another class of innate immune receptors, sequesters MAVS away from RIG-I and thereby prevents mitochondrial antiviral immunity. In this study, we demonstrate that the proteasome PSMA7 (alpha4) subunit associates with MAVS in vivo and in vitro. Expression of PSMA7 results in a potent inhibition of RIG-1 and MAVS-mediated IFN-beta promoter activity; conversely, depletion of PSMA7 with small interference RNA enhances virus-induced type I IFN production, with consequent reduction of virus replication. Furthermore, a striking reduction in the abundance of endogenous MAVS with overexpressed PSMA7 was found and virus infection leads to transient increase in the endogenous PSMA7 protein level. Cumulatively, these results suggest that PSMA7 is a negative regulator of the MAVS-mediated innate immunity that probably serves to attenuate the establishment of an antiviral state during viral infection, highlighting the biological significance of PSMA7-MAVS association as an important cellular regulatory control.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Adaptor Proteins, Signal Transducing / physiology
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Animals
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Cell Line
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Cell Line, Tumor
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Cells, Cultured
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Down-Regulation / genetics
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Down-Regulation / immunology*
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Humans
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Immunity, Innate
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Interferon-beta / antagonists & inhibitors*
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Interferon-beta / biosynthesis
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Interferon-beta / physiology
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / physiology
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Mice
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Mitochondrial Proteins / antagonists & inhibitors*
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Mitochondrial Proteins / physiology
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Proteasome Endopeptidase Complex / deficiency
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / physiology*
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Protein Subunits / deficiency
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Protein Subunits / genetics
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Protein Subunits / physiology
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / physiology
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Vesicular Stomatitis / immunology
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Vesicular Stomatitis / virology
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Vesicular stomatitis Indiana virus / growth & development
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Vesicular stomatitis Indiana virus / immunology*
Substances
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Adaptor Proteins, Signal Transducing
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MAVS protein, human
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Membrane Proteins
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Mitochondrial Proteins
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NLRX1 protein, human
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Protein Subunits
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RRIG1 protein, human
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Tumor Suppressor Proteins
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Interferon-beta
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PSMA7 protein, human
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Proteasome Endopeptidase Complex