T helper cells that produce interleukin 17 (IL-17) are associated with inflammation and the control of certain bacteria. We report here the essential involvement of the adaptor protein Act1 in IL-17 receptor (IL-17R) signaling and IL-17-dependent immune responses. After stimulation with IL-17, recruitment of Act1 to IL-17R required the IL-17R conserved cytoplasmic 'SEFIR' domain, followed by recruitment of the kinase TAK1 and E3 ubiquitin ligase TRAF6, which mediate 'downstream' activation of transcription factor NF-kappaB. IL-17-induced expression of inflammation-related genes was abolished in Act1-deficient primary astroglial and gut epithelial cells. This reduction was associated with much less inflammatory disease in vivo in both autoimmune encephalomyelitis and dextran sodium sulfate-induced colitis. Our data show that Act1 is essential in IL-17-dependent signaling in autoimmune and inflammatory disease.
The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.
Interleukin 17 receptor E (IL-17RE) is an orphan receptor of the IL-17 receptor family. Here we show that IL-17RE is a receptor specific to IL-17C and has an essential role in host mucosal defense against infection. IL-17C activated downstream signaling through IL-17RE-IL-17RA complex for the induction of genes encoding antibacterial peptides as well as proinflammatory molecules. IL-17C was upregulated in colon epithelial cells during infection with Citrobacter rodentium and acted in synergy with IL-22 to induce the expression of antibacterial peptides in colon epithelial cells. Loss of IL-17C-mediated signaling in IL-17RE-deficient mice led to lower expression of genes encoding antibacterial molecules, greater bacterial burden and early mortality during infection. Together our data identify IL-17RE as a receptor of IL-17C that regulates early innate immunity to intestinal pathogens.
Inflammatory cytokines such as interleukin-17 (IL-17) promote inflammatory autoimmune diseases. Although several microRNAs (miRNAs) have been shown to regulate autoimmune pathogenesis by affecting lymphocyte development and function, the role of miRNAs in resident cells present in inflammatory lesions remains unclear. Here we show that miR-23b is downregulated in inflammatory lesions of humans with lupus or rheumatoid arthritis, as well as in the mouse models of lupus, rheumatoid arthritis or multiple sclerosis. IL-17 downregulates miR-23b expression in human fibroblast-like synoviocytes, mouse primary kidney cells and astrocytes and is essential for the downregulation of miR-23b during autoimmune pathogenesis. In turn, miR-23b suppresses IL-17-, tumor necrosis factor α (TNF-α)- or IL-1β-induced NF-κB activation and inflammatory cytokine expression by targeting TGF-β-activated kinase 1/MAP3K7 binding protein 2 (TAB2), TAB3 and inhibitor of nuclear factor κ-B kinase subunit α (IKK-α) and, consequently, represses autoimmune inflammation. Thus, IL-17 contributes to autoimmune pathogenesis by suppressing miR-23b expression in radio-resident cells and promoting proinflammatory cytokine expression.
Interleukin-1 (IL-1) receptor-associated kinase (IRAK) plays an important role in the sequential formation and activation of IL-1-induced signaling complexes. Previous studies showed that IRAK is recruited to the IL-1-receptor complex, where it is hyperphosphorylated. We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1, TAB1, and TAB2, which are preassociated on the membrane before stimulation to form the membrane-associated complex II. The formation of complex II leads to the phosphorylation of TAK1 and TAB2 on the membrane by an unknown kinase, followed by the dissociation of TRAF6-TAK1-TAB1-TAB2 (complex III) from IRAK and consequent translocation of complex III to the cytosol. The formation of complex III and its interaction with additional cytosolic factors lead to the activation of TAK1, resulting in NF-B and JNK activation. Phosphorylated IRAK remains on the membrane and eventually is ubiquitinated and degraded. Taken together, the new data reveal that IRAK plays a critical role in mediating the association and dissociation of IL-1-induced signaling complexes, functioning as an organizer and transporter in IL-1-dependent signaling.Interleukin-1 (IL-1), a major inflammatory cytokine, exerts its biological effects by activating the transcription of various responsive genes (7). The transcription factors activated by IL-1 include NF-B, AP1, and ATF (2,19,20). The IL-1 receptor complex is composed of the type 1 receptor (IL-1R) and the receptor accessory protein (IL-1RAcp) (8-10). Upon IL-1 stimulation, the cytosolic proteins MyD88 (1, 15, 28) and Tollip (3) are recruited to this receptor complex, where they function as adaptors, recruiting IL-1 receptor-associated kinase (IRAK) in turn. IRAK, a serine-threonine kinase, is phosphorylated at the receptor complex and then interacts with TRAF6 (4,5,(12)(13)(14). Phosphorylated IRAK is eventually ubiquitinated and degraded (31). IRAK4 has recently been shown to be an essential component for the IL-1 signaling pathway and proposed to function as an IRAK kinase (11, 24). IRAK and TRAF6 interact with TAK1, a member of the MAP kinase kinase kinase (MAPKKK) family, and two proteins that bind to it, TAB1 and TAB2 (18, 25). The kinase activity of TAK1 is thus activated upon IL-1 stimulation. While genetic studies show that IRAK is required for the activation of TAK1 (26), in vitro biochemical analyses reveal that TRAF6-mediated ubiquitination may also play an important role in TAK1 activation (27). The activation of TAK1 eventually leads to the activation of IB kinase (IKK) by an unknown mechanism. Activated IKK phosphorylates the inhibitory IB proteins, which are then degraded, releasing NF-B to activate transcription in the nucleus (17,22,29,35). Activated TAK1 has also been implicated in the IL-1-induced activation of MKK6 and JNK (18), leading to the phosphorylation and activation of ATF ...
The Toll-interleukin-1 receptor (TIR) 1 superfamily, a large family of proteins defined by the presence of an intracellular TIR domain, plays crucial roles in the immune response. This superfamily can be divided into two main subgroups, based on the extracellular domains: the immunoglobulin (Ig) domaincontaining receptors (1), and the leucine-rich repeat motifcontaining receptors (2). The Ig domain subgroup includes IL-1R1, IL-18 receptor, T1/ST2, and SIGIRR. IL-1 has been demonstrated to be a key player in the immune response and inflammatory response at both local and systemic levels by activating gene expression of such genes as MIP-2, KC, and C-reactive protein. IL-18 plays important roles in promoting Th1 cell differentiation and natural killer cell activation. T1/ ST2 (3) and SIGIRR (4), also known as TIR8 (5), have been shown to function as negative regulators for Toll-IL-1R-mediated signaling. The leucine-rich repeat motif subgroup consists of at least 11 Toll-like receptors (TLRs) (2, 6 -10). These receptors have received intense attention because different TLRs were found to be activated by specific pathogen products (8,(11)(12)(13)(14)(15)(16).Due to the similarity in their intracellular domain, the Toll-IL-1 receptors employ related yet distinct signaling components and downstream pathways. Genetic and biochemical studies revealed that IL-1R mediates a very complex pathway involving a cascade of kinases organized by multiple adapter molecules into signaling complexes, leading to activation of the transcription factors NF-B, ATF, and AP-1 (17-19). Based on published studies (20 -23), a model of the IL-1 pathway is postulated. Upon IL-1 stimulation, adapter molecule MyD88 (24) is first recruited to the IL-1 receptor, followed by the recruitment of two serine-threonine kinases, IRAK4 (25,26) and IRAK (27,28), and the adapter TRAF6 (29), resulting in the formation of the receptor complex (Complex I). During the formation of Complex I, IRAK and IRAK4 are activated, leading to the hyperphosphorylation of IRAK. Pellino 1⅐IRAK4⅐IRAK⅐TRAF6 complex is then formed, releasing these signaling molecules from the receptor (20). The released components interact with the membrane bound pre-associated TAK1⅐TAB1⅐TAB2⅐TAB3 (21, 23), resulting in the formation of Complex II (IRAK⅐TRAF6⅐TAK1⅐TAB1⅐TAB2⅐TAB3), followed by the translocation of TRAF6⅐TAK1⅐TAB1⅐TAB2⅐TAB3 (Complex III) from the membrane to the cytosol. The translocated Complex III interacts with additional factors in the cytosol, leading to TAK1 activation. It has been implicated that TRAF6 functions as part of a unique E3 complex, mediating TAK1 activation through nonclassical ubiquitination catalyzed by the ubiquitination proteins Ubc13 and Uev1A (30, 31). Once activated, TAK1 can directly phosphorylate IKK and mitogenactivated protein kinase kinase 6, leading to the activation of both the JNK and NF-B signaling pathways (32-35). In addition to TAK1, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 and 3 have also been i...
Highlights d Tumor-secreted CTSC promotes breast-to-lung metastasis by regulating neutrophils d CTSC activates membrane-bound PR3 of neutrophils to upregulate IL-1b secretion d CTSC enhances neutrophil recruitment into metastatic niches and induces NETosis d Targeting CTSC with AZD7986 effectively inhibits lung metastasis in mice
Interleukin (IL)-17, a proinflammatory cytokine mainly produced by T-helper-17 (T H 17) lineage, is required for host defense against bacteria and fungus infection and plays a critical role in the pathogenesis of inflammatory and autoimmune diseases. Act1 is an essential adaptor molecule in IL-17-mediated signaling pathway, recruited to IL-17 receptor (IL-17R) upon IL-17 stimulation through SEFIR-SEFIR domain interaction. Here we report that Act1 is a novel bona fide U-box E3 ubiquitin ligase, whose activity is essential for IL-17-mediated signaling pathways (including nuclear factor kappa B (NFκB), and partially required for Jun N-terminal Kinase (JNK) and extracellular signal-regulated kinase (ERK) activation) and inflammatory gene expression (KC (CXCL1), granulocyte macrophage colony stimulating factor (GM-CFS ) and IL-6) in mammalian cells. By utilizing Ubc13/Uev1A E2 complex, Act1 mediates Lys 63-linked ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6), an important signaling component of IL-17-mediated signaling pathway. Deletion and point mutations of the Act1 U-box abolish Act1-mediated ubiquitination of TRAF6 and impair the ability of Act1 to restore IL-17-dependent signaling and inflammatory gene expression in Act1 −/− mouse embryonic fibroblasts (MEFs). Importantly, we demonstrate that the Lys 124 residue of TRAF6 is critical for efficient Act1-mediated TRAF6 ubiquitination and for the ability of TRAF6 to mediate IL-17-induced NFκB activation. Thus Act1 mediates IL-17-induced signaling pathways through its E3 ubiquitin ligase activity and TRAF6 is a critical substrate of Act1, indicating the importance of protein ubiquitination in IL-17-dependent inflammatory response.
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