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PMID:22079989

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Citation

Ng, MH, Ho, TH, Kok, KH, Siu, KL, Li, J and Jin, DY (2011) MIP-T3 is a negative regulator of innate type I IFN response. J. Immunol. 187:6473-82

Abstract

TNFR-associated factor (TRAF) 3 is an important adaptor that transmits upstream activation signals to protein kinases that phosphorylate transcription factors to induce the production of type I IFNs, the important effectors in innate antiviral immune response. MIP-T3 interacts specifically with TRAF3, but its function in innate IFN response remains unclear. In this study, we demonstrated a negative regulatory role of MIP-T3 in type I IFN production. Overexpression of MIP-T3 inhibited RIG-I-, MDA5-, VISA-, TBK1-, and IKKε-induced transcriptional activity mediated by IFN-stimulated response elements and IFN-β promoter. MIP-T3 interacted with TRAF3 and perturbed in a dose-dependent manner the formation of functional complexes of TRAF3 with VISA, TBK1, IKKε, and IFN regulatory factor 3. Consistent with this finding, retinoic acid-inducible gene I- and TBK1-induced phosphorylation of IFN regulatory factor 3 was significantly diminished when MIP-T3 was overexpressed. Depletion of MIP-T3 facilitated Sendai virus-induced activation of IFN production and attenuated the replication of vesicular stomatitis virus. In addition, MIP-T3 was found to be dissociated from TRAF3 during the course of Sendai virus infection. Our findings suggest that MIP-T3 functions as a negative regulator of innate IFN response by preventing TRAF3 from forming protein complexes with critical downstream transducers and effectors.

Links

PubMed Online version:10.4049/jimmunol.1100719

Keywords

Animals; Cercopithecus aethiops; Down-Regulation/genetics; Down-Regulation/immunology; HEK293 Cells; Humans; Immunity, Innate/genetics; Interferon Type I/antagonists & inhibitors; Interferon Type I/biosynthesis; Interferon-beta/genetics; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins/genetics; Microtubule-Associated Proteins/metabolism; Microtubule-Associated Proteins/physiology; Promoter Regions, Genetic/immunology; Protein Binding/immunology; Respirovirus Infections/immunology; Respirovirus Infections/metabolism; Respirovirus Infections/virology; Sendai virus/immunology; Signal Transduction/genetics; Signal Transduction/immunology; TNF Receptor-Associated Factor 3/antagonists & inhibitors; TNF Receptor-Associated Factor 3/metabolism; Vero Cells

Significance

Annotations

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

MOUSE:MIPT3

acts_upstream_of_or_within

GO:0032688: negative regulation of interferon-beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:MIPT3

acts_upstream_of_or_within

GO:0050687: negative regulation of defense response to virus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

HUMAN:MIPT3

involved_in

GO:0050687: negative regulation of defense response to virus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MIPT3

involved_in

GO:0001933: negative regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MIPT3

involved_in

GO:0031333: negative regulation of protein complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MIPT3

involved_in

GO:0032480: negative regulation of type I interferon production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MIPT3

GO:0050687: negative regulation of defense response to virus

ECO:0000315:

P

Fig. 7ABC

complete
CACAO 3043

HUMAN:MIPT3

GO:0001933: negative regulation of protein phosphorylation

ECO:0000315:

P

Fig. 6

complete
CACAO 3044

HUMAN:MIPT3

GO:0032480: negative regulation of type I interferon production

ECO:0000315:

P

Fig. 1

complete
CACAO 3045

HUMAN:MIPT3

GO:0031333: negative regulation of protein complex assembly

ECO:0000315:

P

Fig. 4(A-D), and Fig. 5

complete
CACAO 3046

MOUSE:MIPT3

involved_in

GO:0050687: negative regulation of defense response to virus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MIPT3

acts_upstream_of_or_within

GO:0032688: negative regulation of interferon-beta production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MIPT3

acts_upstream_of_or_within

GO:0050687: negative regulation of defense response to virus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

regulates_o_occurs_in:(CL:0000057)

Seeded From UniProt

complete

MOUSE:MIPT3

GO:0050687: negative regulation of defense response to virus

ECO:0000315:

P

Fig. 7DEFG

complete
CACAO 3042


See also

References

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