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PMID:19211564

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Citation

Bamming, D and Horvath, CM (2009) Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I, and LGP2. J. Biol. Chem. 284:9700-12

Abstract

Intracellular pattern recognition receptors MDA5, RIG-I, and LGP2 are essential components of the cellular response to virus infection and are homologous to the DEXH box subfamily of RNA helicases. However, the relevance of helicase activity in the regulation of interferon production remains elusive. To examine the importance of the helicase domain function for these signaling proteins, a series of mutations targeting conserved helicase sequence motifs were analyzed for enzymatic activity, RNA binding, interferon induction, and antiviral signaling. Results indicate that all targeted motifs are required for ATP hydrolysis, but a subset is involved in RNA binding. The enzymatically inactive mutants differed in their signaling ability. Notably, mutations to MDA5 motifs I, III, and VI and RIG-I motif III produced helicase proteins with constitutive antiviral activity, whereas mutations in RIG-I motif V retained ATP hydrolysis but failed to mediate signal transduction. These findings demonstrate that type I interferon production mediated by full-length MDA5 and RIG-I is independent of the helicase domain catalytic activity. In addition, neither enzymatic activity nor RNA binding was required for negative regulation of antiviral signaling by LGP2, supporting an RNA-independent interference mechanism.

Links

PubMed PMC2665091 Online version:10.1074/jbc.M807365200

Keywords

Adenosine Triphosphate/chemistry; Amino Acid Motifs; Amino Acid Sequence; Animals; Antiviral Agents/pharmacology; DEAD-box RNA Helicases/metabolism; Humans; Insects; Molecular Sequence Data; Protein Binding; RNA Helicases/metabolism; Sequence Homology, Amino Acid; Signal Transduction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DDX58

enables

GO:0003724: RNA helicase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DDX58

enables

GO:0016887: ATP hydrolysis activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX58

enables

GO:0003724: RNA helicase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX58

enables

GO:0016887: ATP hydrolysis activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DHX58

involved_in

GO:0039528: cytoplasmic pattern recognition receptor signaling pathway in response to virus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IFIH1

enables

GO:0003724: RNA helicase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IFIH1

enables

GO:0016887: ATP hydrolysis activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IFIH1

involved_in

GO:0039530: MDA-5 signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0032728: positive regulation of interferon-beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0039529: RIG-I signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DDX58

enables

GO:0003727: single-stranded RNA binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:DDX58

enables

GO:0003725: double-stranded RNA binding

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IFIH1

involved_in

GO:0032728: positive regulation of interferon-beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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