Overactive TH17 responses are tightly linked to the development of autoimmunity, yet the factors that negatively regulate differentiation of this lineage remain unknown. Here, we report that T-bet suppresses the development of the TH17 cell lineage by inhibiting the transcription of Rorc. T-bet interacts with the transcription factor Runx1 and this interaction blocks Runx1-mediated transactivation of Rorc. T-bet residue Tyr304 is required for T-bet-Runx1 complex formation, for blocking Runx1 activity and for inhibiting the TH17 differentiation program. These data reinforce the concept of master regulators that shape immune responses by simultaneously activating one genetic program while silencing the activity of competing regulators in a common progenitor cell.
Bone morphogenetic proteins (Bmps) are members of the transforming growth factor  (TGF) superfamily that play critical roles during mouse embryogenesis. Signaling by Bmp receptors is mediated mainly by Smad proteins. In this study, we show that a targeted null mutation of Ecsit, encoding a signaling intermediate of the Toll pathway, leads to reduced cell proliferation, altered epiblast patterning, impairment of mesoderm formation, and embryonic lethality at embryonic day 7.5 (E7.5), phenotypes that mimic the Bmp receptor type1a ( The transforming growth factor  (TGF) superfamily comprises a large number of secreted polypeptide factors, with >30 members in mammals and about a dozen in worms and flies. TGFs control numerous cellular functions and regulate many developmental and homeostatic processes. However, a simple scheme lies at the core of all TGF signaling pathways. The receptor for TGF is a complex of two distinct transmembrane proteins, known as type I and type II receptors, with serine/threonine kinase activity within their cytoplasmic domains. Ligand binding to the type II receptor induces the association, phosphorylation, and activation of the type I receptor. The activated type I receptor then signals through the Smad family of signal transducers. Smad proteins can be divided into three classes: receptor-regulated Smads or R-Smads (Smad1, 2, 3, 5, 8); co-Smad (Smad4); and inhibitory Smads or I-Smads (Smad6 and 7). After stimulation, R-Smads are phosphorylated by type I receptors, detach from the receptor complex, associate with Smad4, and accumulate in the nucleus, where they regulate gene expression by interacting with various cofactors. Smad access to target genes and the recruitment of transcriptional coactivators or corepressors to these genes depend on cell-type-specific cofactors. Although many Smad cofactors have been identified for the TGF pathways, very few are known for the Bmp pathways (Wrana 2000;Shi and Massague 2003).Genetic evidence has shown that Bmp4 plays pivotal roles in the gastrulation of mouse embryo, a process that lays down the future body plan (Lu et al. 2001). Bmp4 regulates the proliferation, survival, and patterning of the epiblast; the induction of primordial germ cell precursors; and formation of the mesoderm (Mishina et al. 1995;Winnier et al. 1995;Lawson et al. 1999). Bmp4 signals through Bmpr1a, a type I Bmp receptor, to induce the up-regulation of target genes including Tlx2, a homeobox gene that is a critical effector of Bmp signaling
The protein kinase TAK1 (transforming growth factor-beta-activated kinase 1), which has been implicated in the activation of MAPK (mitogen-activated protein kinase) cascades and the production of inflammatory mediators by LPS (lipopolysaccharide), IL-1 (interleukin 1) and TNF (tumour necrosis factor), comprises the catalytic subunit complexed to the regulatory subunits, termed TAB (TAK1-binding subunit) 1 and either TAB2 or TAB3. We have previously identified a feedback-control mechanism by which p38alpha MAPK down-regulates TAK1 and showed that p38alpha MAPK phosphorylates TAB1 at Ser(423) and Thr(431). In the present study, we identified two IL-1-stimulated phosphorylation sites on TAB2 (Ser(372) and Ser(524)) and three on TAB3 (Ser(60), Thr(404) and Ser(506)) in human IL-1R cells [HEK-293 (human embryonic kidney) cells that stably express the IL-1 receptor] and MEFs (mouse embryonic fibroblasts). Ser(372) and Ser(524) of TAB2 are not phosphorylated by pathways dependent on p38alpha/beta MAPKs, ERK1/2 (extracellular-signal-regulated kinase 1/2) and JNK1/2 (c-Jun N-terminal kinase 1/2). In contrast, Ser(60) and Thr(404) of TAB3 appear to be phosphorylated directly by p38alpha MAPK, whereas Ser(506) is phosphorylated by MAPKAP-K2/MAPKAP-K3 (MAPK-activated protein kinase 2 and 3), which are protein kinases activated by p38alpha MAPK. Studies using TAB1(-/-) MEFs indicate important roles for TAB1 in recruiting p38alpha MAPK to the TAK1 complex for the phosphorylation of TAB3 at Ser(60) and Thr(404) and in inhibiting the dephosphorylation of TAB3 at Ser(506). TAB1 is also required to induce TAK1 catalytic activity, since neither IL-1 nor TNFalpha was able to stimulate detectable TAK1 activity in TAB1(-/-) MEFs. Surprisingly, the IL-1 and TNFalpha-stimulated activation of MAPK cascades and IkappaB (inhibitor of nuclear factor kappaB) kinases were similar in TAB1(-/-), MEKK3(-/-) [MAPK/ERK (extracellular-signal-regulated kinase) kinase kinase 3] and wild-type MEFs, suggesting that another MAP3K (MAPK kinase kinase) may mediate the IL-1/TNFalpha-induced activation of these signalling pathways in TAB1(-/-) and MEKK3(-/-) MEFs.
Activation of NF-B requires two highly related kinases named IKK␣ and IKK that share identity in the nature and positioning of their structural domains. Despite their similarity, the kinases are functionally divergent, and we therefore sought to identify any structural features specific for IKK␣ or IKK. We performed bioinformatics analysis, and we identified a region resembling a ubiquitin-like domain (UBL) that exists only in IKK and that we named the UBL-like domain (ULD). Deletion of the ULD rendered IKK catalytically inactive and unable to induce NF-B activity, and overexpression of only the ULD dose-dependently inhibited tumor necrosis factor-␣-induced NF-B activity. The ULD could not be functionally replaced within IKK by ubiquitin or the corresponding region of IKK␣, whereas deletion of the equivalent section of IKK␣ did not affect its catalytic activity against IB␣ or its activation by NF-B-inducing kinase. We identified five residues conserved among the larger family of UBL-containing proteins and IKK, and alanine scanning revealed that the leucine at position 353 (Leu 353 ) is absolutely critical for IKK-induced NF-B activation. Most intriguingly, the L353A mutant was catalytically active but, unlike wildtype IKK, formed a stable complex with the NF-B p65 subunit. Our findings therefore establish the ULD as a critical functional domain specific for IKK that might play a role in dissociating IKK from p65.
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