Journal
JOURNAL OF IMMUNOLOGY
Volume 187, Issue 12, Pages 6473-6482Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100719
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Funding
- Hong Kong Research Grants Council-National Natural Science Foundation of China [N-HKU 720/08]
- Association for International Cancer Research [07-0424]
- Hong Kong Research Grants Council Collaborative Research Fund [HKU 7/CRF09]
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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 IKK epsilon-induced transcriptional activity mediated by IFN-stimulated response elements and IFN-beta promoter. MIP-T3 interacted with TRAF3 and perturbed in a dose-dependent manner the formation of functional complexes of TRAF3 with VISA, TBK1, IKK epsilon, 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. The Journal of Immunology, 2011, 187: 6473-6482.
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