TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.

Nuclear factor-B (NF-B) is a transcription factor critical for key cellular processes, including immune response, apoptosis, and cell cycle progression. A yeast two-hybrid screening, using the Rel homology domain (RHD) of the p65 subunit (RelA) of NF-B as bait, led to the isolation of PIAS3, previously identified as a specific inhibitor of STAT3. We show that PIAS3 can directly associate with p65 using an in vitro pull-down and in vivo coimmunoprecipitation assays. When overexpressed, PIAS3 inhibits NF-B-dependent transcription induced by treatment with tumor necrosis factor ␣ (TNF-␣) or interleukin-1␤ or by overexpression of TNF family receptors such as RANK, TNFR1, and CD30 or signal transducers of TNF receptor-associated factors (TRAFs), including TRAF2, TRAF5, and TRAF6. Downregulation of PIAS3 by RNA interference reverses its effect on TNF-␣-mediated NF-B activation. We found that an N-terminal region of PIAS3 is necessary for both the interaction with p65 and the transcriptional suppression activity. In addition, we found that an LXXLL coregulator signature motif located within the N-terminal region of PIAS3 is the minimal requirement for the interaction with p65. Furthermore, we demonstrate that PIAS3 interferes with p65 binding to the CBP coactivator, thereby resulting in a decreased NF-B-dependent transcription. Taken together, these data suggest that PIAS3 may function in vivo as a modulator in suppressing the transcriptional activity of p65. NF-B1 is an inducible cellular transcription factor that plays a critical role in the expression of a variety of genes involved in immune and inflammatory responses and cell survival (1-3). There are five known members of the mammalian NF-B/Rel family: p65 (RelA), c-Rel, RelB, p50 (NF-B1), and p52 (NF-B2). These proteins share a conserved 300-amino acid region known as the Rel homology domain (RHD), which is responsible for DNA binding, dimerization, and nuclear translocation of NF-B (4 -6). In most cells, Rel family members form hetero-and homodimers with distinct specificities in various combinations. p65, RelB, and c-Rel are transcriptionally active members of the NF-B family, whereas p50 and p52 primarily serve as the DNA binding subunits (4 -6). The most widely studied and most abundant form of NF-B is the heterodimer of p50 and p65.A common feature of the regulation of NF-B is the sequestration in the cytoplasm as an inactive complex physically associated with a class of inhibitory molecules known as IBs (7). Treatment of cells with a variety of inducers such as phorbol esters, interleukin-1 (IL-1), and tumor necrosis factor-␣ (TNF-␣) results in phosphorylation, ubiquitination, and degradation of the IB proteins (2, 8, 9). The degradation of IB proteins exposes the nuclear localization sequence in the remaining NF-B dimers, which in turn leads to a rapid translocation of NF-B to nucleus where it activates target genes by binding to cognate DNA regulatory elements (4 -6).A recent work has shown that NF-B-dependent transcription requires the function of transc...

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Microsatellite instability (MSI) is a critical mechanism that drives genetic aberrations in cancer. To identify the entire MS mutation, we performed the first comprehensive genome-and transcriptome-wide analyses of mutations associated with MSI in Korean gastric cancer cell lines and primary tissues. We identified 18,377 MS mutations of five or more repeat nucleotides in coding sequences and untranslated regions of genes, and discovered 139 individual genes whose expression was down-regulated in association with UTR MS mutation. In addition, we found that 90.5% of MS mutations with deletions in gene regions occurred in UTRs. This analysis emphasizes the genetic diversity of MSI-H gastric tumors and provides clues to the mechanistic basis of instability in microsatellite unstable gastric cancers.