Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Function of Act1 in IL-17 family signaling and autoimmunity.

ABSTRACT: The maintenance of immune homeostasis requires the delicate balance between response to foreign antigens and tolerance to self. As such, when this balance is disrupted, immunodeficiency or autoimmunity may manifest. The adaptor molecule known as Act1 is a critical mediator of IL-17 receptor receptor family signaling. This chapter will detail the current understanding of Act1 's role in signal transduction as well as address the fundamental role of Act1 in autoimmunity. At the molecular level Act1 interacts with IL-17 R through the conserved SEFIR domain, binds TRAF proteins and exerts E3 ubiquitin ligase activity. In in vivo models, Act1 deficiency provides protection against experimental autoimmune diseases, such as colitis and EAE. Yet mice lacking in Act1 develop spontaneous autoimmune diseases. Indeed, the utility of Act1 seems to rely on the specific cell type expression that may determine the pathway that Act1 mediates.

SUBMITTER: Wu L

PROVIDER: S-EPMC6873457 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Function of Act1 in IL-17 family signaling and autoimmunity.

Wu Ling L Zepp Jarod J Li Xiaoxia X

Advances in experimental medicine and biology 20120101

The maintenance of immune homeostasis requires the delicate balance between response to foreign antigens and tolerance to self. As such, when this balance is disrupted, immunodeficiency or autoimmunity may manifest. The adaptor molecule known as Act1 is a critical mediator of IL-17 receptor receptor family signaling. This chapter will detail the current understanding of Act1 's role in signal transduction as well as address the fundamental role of Act1 in autoimmunity. At the molecular level Act ...[more]

PMID: 21948371

Similar Datasets

IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling.

Project description:Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3' untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3' UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.

| S-EPMC6082628 | biostudies-literature

Act1, a U-box E3 ubiquitin ligase for IL-17 signaling.

Project description:Interleukin-17 (IL-17), a proinflammatory cytokine mainly produced by cells of the T helper 17 (T(H)17) lineage, is required for host defense against bacterial and fungal infections and plays a critical role in the pathogenesis of inflammatory and autoimmune diseases. Act1 is an essential adaptor molecule in IL-17-mediated signaling and is recruited to the IL-17 receptor (IL-17R) upon IL-17 stimulation through an interaction between its SEFIR domain and that of the IL-17R. Here, we report that Act1 is a U-box E3 ubiquitin ligase and that its activity is essential for IL-17-mediated signaling pathways. Through the use of the Ubc13-Uev1A E2 complex, Act1 mediated the lysine-63-linked ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6), a component of IL-17-mediated signaling. Deletion and point mutations of the Act1 U-box abolished Act1-mediated ubiquitination of TRAF6 and impaired the ability of Act1 to restore IL-17-dependent signaling and expression of target genes in Act1(-/-) mouse embryonic fibroblasts. We also showed that the lysine-124 residue of TRAF6 was critical for efficient Act1-mediated ubiquitination of TRAF6 and for the ability of TRAF6 to mediate IL-17-induced activation of nuclear factor kappaB. Thus, we propose that Act1 mediates IL-17-induced signaling pathways through its E3 ubiquitin ligase activity and that TRAF6 is a critical substrate of Act1, which indicates the importance of protein ubiquitination in the IL-17-dependent inflammatory response.

| S-EPMC3182834 | biostudies-literature

The differential regulation of human ACT1 isoforms by Hsp90 in IL-17 signaling.

Project description:IL-17 is a proinflammatory cytokine implicated in the pathogenesis of autoimmune diseases including psoriasis. ACT1 is an essential adaptor molecule in the IL-17 signaling pathway. A missense single nucleotide polymorphism (rs33980500; SNP-D10N) that resulted in the substitution of an asparagine for an aspartic acid at position 10 of ACT1 (ACT1-D10N) is associated with psoriasis susceptibility. Due to alternative splicing in humans, SNP-D10N encodes two mutated ACT1 proteins, ACT1-D10N and ACT1-D19N. Although both ACT1 isoforms are Hsp90 client proteins, the nine additional amino acids in ACT1-D19N provide an additional Hsp90 binding site that is absent in ACT1-D10N. Therefore, whereas ACT1-D10N is a dead protein that is unable to transduce IL-17 signals for gene expression, ACT1-D19N is fully responsive to IL-17. Intriguingly, the two ACT1 isoforms are differentially expressed in ACT1(D10N/D10N) fibroblasts and T cells. Fibroblasts express both isoforms equally, enabling ACT1-D19N to compensate for the loss of ACT1-D10N function. ACT1(D10N/D10N) T cells, however, express predominantly ACT1-D10N. Lacking this compensatory mechanism, ACT1(D10N/D10N) T cells behave like ACT1-deficient T cells, exhibiting a dysregulated and hyperactive Th17 phenotype with overproduction of IL-22 and IL-17. The hyperactive Th17 response combined with fully responsive fibroblasts likely synergized to contribute to psoriasis susceptibility in SNP-D10N patients.

| S-EPMC4119565 | biostudies-literature

A Novel Nuclear Function for the Interleukin-17 Signaling Adaptor Protein Act1.

Project description:In the context of the human airway, interleukin-17A (IL-17A) signaling is associated with severe inflammation, as well as protection against pathogenic infection, particularly at mucosal surfaces such as the airway. The intracellular molecule Act1 has been demonstrated to be an essential mediator of IL-17A signaling. In the cytoplasm, it serves as an adaptor protein, binding to both the intracellular domain of the IL-17 receptor as well as members of the canonical nuclear factor kappa B (NF-?B) pathway. It also has enzymatic activity, and serves as an E3 ubiquitin ligase. In the context of airway epithelial cells, we demonstrate for the first time that Act1 is also present in the nucleus, especially after IL-17A stimulation. Ectopic Act1 expression can also increase the nuclear localization of Act1. Act1 can up-regulate the expression and promoter activity of a subset of IL-17A target genes in the absence of IL-17A signaling in a manner that is dependent on its N- and C-terminal domains, but is NF-?B independent. Finally, we show that nuclear Act1 can bind to both distal and proximal promoter regions of DEFB4, one of the IL-17A responsive genes. This transcriptional regulatory activity represents a novel function for Act1. Taken together, this is the first report to describe a non-adaptor function of Act1 by directly binding to the promoter region of IL-17A responsive genes and directly regulate their transcription.

| S-EPMC5056742 | biostudies-literature

IL-17-induced NF-kappaB activation via CIKS/Act1: physiologic significance and signaling mechanisms.

Project description:Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation of transcription factor NF-κB; it is not known whether CIKS and/or NF-κB are required for all gene induction events. Here we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas NF-κB is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated NF-κB activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required for NF-κB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases.

| S-EPMC3075635 | biostudies-literature

IL-17 family: cytokines, receptors and signaling.

Project description:The interleukin 17 (IL-17) family, a subset of cytokines consisting of IL-17A-F, plays crucial roles in host defense against microbial organisms and in the development of inflammatory diseases. Although IL-17A is the signature cytokine produced by T helper 17 (Th17) cells, IL-17A and other IL-17 family cytokines have multiple sources ranging from immune cells to non-immune cells. The IL-17 family signals via their correspondent receptors and activates downstream pathways that include NF?B, MAPKs and C/EBPs to induce the expression of anti-microbial peptides, cytokines and chemokines. The proximal adaptor Act1 is a common mediator during the signaling of all IL-17 cytokines so far and is thus involved in IL-17 mediated host defense and IL-17-driven autoimmune conditions. This review will give an overview and recent updates on the IL-17 family, the activation and regulation of IL-17 signaling as well as diseases associated with this cytokine family.

| S-EPMC3867811 | biostudies-literature

IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner.

Project description:Estrogen-deficient osteoporosis may be an inflammatory disorder and we therefore asked if IL-17 participates in its pathogenesis. Deletion of the principal IL-17 receptor (IL-17RA) protects mice from ovariectomy (OVX)-induced bone loss. Further supporting a central role of IL-17 in its pathogenesis, OVX-induced osteoporosis is prevented by a blocking antibody targeting the cytokine. IL-17 promotes osteoclastogenesis by stimulating RANK ligand (RANKL) expression by osteoblastic cells, mediated by the IL-17RA SEFIR/TILL domain. Estrogen deprivation, however does not enhance IL-17RA mRNA expression by osteoblasts or in bone, but augments that of Act1, an IL-17RA-interacting protein and signaling mediator. Similar to IL-17RA(-/-) mice, those lacking Act1 are protected from OVX-induced bone loss. Also mirroring IL-17RA-deficiency, absence of Act1 in osteoblasts, but not osteoclasts, impairs osteoclastogenesis via dampened RANKL expression. Transduction of WT Act1 into Act1(-/-) osteoblasts substantially rescues their osteoclastogenic capacity. The same construct, however, lacking its E3 ligase U-box or its SEFIR domain, which interacts with its counterpart in IL-17RA, fails to do so. Estrogen deprivation, therefore, promotes RANKL expression and bone resorption in association with upregulation of the IL-17 effector, Act1, supporting the concept that post-menopausal osteoporosis is a disorder of innate immunity.

| S-EPMC3640304 | biostudies-literature

IL-17-induced NF-kB activation via CIKS/Act1: Physiologic significance and signaling mechanisms

Project description:Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of the adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and to activation of the transcription factor NF-kB; it is not known whether CIKS and/or NF-kB are required for all gene induction events. Here we report that CIKS is essential for all IL-17 induced immediate-early genes in primary mouse embryo fibroblasts, while NF-kB is profoundly involved. We also identify a novel sub-domain in the N-terminus of CIKS that is essential for IL-17-mediated NF-kB activation. This domain is both necessary and sufficient for the interaction between CIKS and TRAF6, an adaptor required for NF-kB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases. Keywords: strain comparisons strain comparisons

2011-10-18 | E-GEOD-24873 | biostudies-arrayexpress

Act1 modulates mRNA metabolism upon IL-17 stimulation

Project description:The IL-17 receptor adaptor molecule Act1, an RNA binding protein, plays a critical role in IL-17-mediated cancer progression. Here we report a novel mechanism for how IL-17/Act1 induces chemoresistance by modulating redox homeostasis through epitranscriptomic regulation of antioxidant RNA metabolism. Transcriptome-wide mapping of direct Act1-RNA interactions revealed that Act1 binds to the 5'UTR of antioxidant mRNAs and Wilms' tumor 1-associating protein (WTAP), a key regulator in m6A methyltransferase complex. Strikingly, Act1's binding sites are located in proximity to m6A modification sites, which allows Act1 to promote the recruitment of elF3G for cap-independent translation. Loss of Act1’s RNA binding activity or Wtap knockdown abolished IL-17-induced m6A modification and translation of Wtap and antioxidant mRNAs, indicating a feedforward mechanism of Act1-WTAP loop. We then developed antisense oligonucleotides (Wtap ASO) that specifically disrupts Act1’s binding to Wtap mRNA, abolishing IL-17/Act1-WTAP-mediated antioxidant protein production during chemotherapy. Wtap ASO substantially increased the antitumor efficacy of cisplatin, demonstrating a potential therapeutic strategy for chemoresistance.

2024-06-06 | GSE263835 | GEO

Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells.

Project description:Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-?B activator 1 (Act1), the key transducer of IL-17 receptor signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes and astrocytes) results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deletion of Act1 in neurons or mature oligodendrocytes, and Act1 deletion in astrocytes only modestly affected disease course. Deletion of Act1 in NG2(+) glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2(+) glial cells. IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2(+) glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis.

| S-EPMC4106025 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data