MIP-T3 Is a Negative Regulator of Innate Type I IFN Response

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.

Characterization of the <i>TRAF3IP1</i> gene in Yesso scallop (<i>Patinopecten yessoensis</i>) and its expression in response to bacterial challenge

“…TRAF3IP1 is conserved from worms to human and interacts constitutively with TRAF3 through a C-terminal coiled-coil region (Ling and Goeddel, 2000;Guo et al, 2010). A previous study has shown that TRAF3IP1 is a cellular inhibitor of the innate IFN response that impedes TRAF3 complex formation with critical downstream transducers and effectors (Ng et al, 2011), which supports the notion that TRAF3IP1 is biologically important in the regulation of immune responses. Moreover, TRAF3IP1 was also shown to bind microtubules and play an important role in the regulation of cytoskeleton dynamics in cells (Kunitomo and lino, 2007;Guo et al, 2010).…”

“…A previous study has shown that TRAF3IP1 interacts specifically with TRAF3 and prevents it from forming protein complexes with downstream transducer and effector proteins (Ng et al, 2011). Here, transcription levels of several TRAFs measured in different bivalve species with different bacterial challenges, and resulting from bibliographic analysis, are summarized in Table 2.…”

Hantavirus GnT Elements Mediate TRAF3 Binding and Inhibit RIG-I/TBK1-Directed Beta Interferon Transcription by Blocking IRF3 Phosphorylation

“…Collectively, our findings define GnT interactions that inhibit IFN-␤ transcriptional induction by regulating the activation of IRF3/NF-B transcription factors. However, numerous potential effectors that impact TBK1-IRF3 signaling responses (36,40,62,74) require further investigation to define regulatory interactions targeted by discrete hantavirus GnTs.…”

Integration of biological data by kernels on graph nodes allows prediction of new genes involved in mitotic chromosome condensation

“…Eleven of the 32 genes score as high-confidence positives and therefore open new avenues for experiments. For example, TRAF3IP1 is involved in primary cilium formation (Berbari et al ., 2011) and has also been implicated in signal transduction pathways (Niu et al ., 2003; Ng et al ., 2011) but not in chromosome condensation. Our study also clarifies several leads from the literature that had not been followed up.…”