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Act1 modulates mRNA metabolism upon IL-17 stimulation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE263835 | GEO | 2024/06/06

REPOSITORIES: GEO

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RNAseq of Mouse Embryonic Fibroblasts(MEFs) stimulated by IL-17

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 | GSE263596 | GEO

Dual role of Act1 in keratinocyte differentiation and host defense: TRAF3IP2 silencing alters keratinocyte differentiation while inhibiting IL-17 responses

Project description:TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, a ubiquitin ligase that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible shRNA targeting TRAF3IP2. Tet exposure for seven days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up, >1.5-fold, p<0.05). Gene Ontology analysis revealed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being downregulated and late differentiation genes (SPRR2, SPRR3, LCE3) being upregulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses, while increasing basal levels and TRAF3IP2 silencing-dependent upregulation of late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk.

2017-08-21 | GSE86451 | GEO

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

Identification of LncRNA TRAF3IP2-AS1 as a key regulator of IL-17 signaling through the SRSF10-IRF1-Act1 axis in autoimmune diseases

Project description:Our study indicates that lncRNA TRAF3IP2-AS1 serving as a negative regulator of Act1 transcriptional expression and IL-17 signaling pathway activity,recruits SRSF10 to downregulate the transcription of IRF1, which is itself a transcriptional factor for Act1. And the psoriasis-susceptible variant A4165G of TRAF3IP2-AS1 is a gain-of-function mutant that binds more strongly than the wild-type form to SRSF10. It means that TRAF3IP2-AS1 or SRSF10 may be a good target for the treatment of human IL-17-related autoimmune diseases.

2021-01-30 | GSE165781 | GEO

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

2011-10-19 | GSE24873 | GEO

Systematic analysis of IL-17 receptor signalosome reveals a robust regulatory feedback loop

Project description:IL-17 mediates immune protection from fungi and bacteria as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of LUBAC as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.

2020-07-15 | PXD019020 | Pride

Macrophage-specific Act1 Knockdown Promoted Adenoma-Adenocarcinoma Transition in Apcmin+/- Mice via Activation of the CXCL9/10-CXCR3 axis

Project description:macrophages involve in colorectal adenocarcinoma transition. Mouse MC38 colorectal cancer cells were co-cultured with BMDM from both anti-Act1 and Wildtype mice. MC38 cells have higher migration speed and express higher EMT markers including Snail, E-cadherins, and Twist after co-culture with anti-Act1 macrophage. Expression profiling by high throughput sequencing highlighted that by co-culturing with MC38 cells, anti-Act1 macrophage increase proinflammatory cytokines secretion and consequently activates cytokines receptor signaling pathway. Specifically, we identified the mechanism where CXCL9/10 from anti-Act1 macrophage interacted with CXCR3 receptor in MC38 cell to promote MC38 migration as well as EMT. Besides, coculturing with MC38 cells enhanced expressions of PD-L1 and MDSCs markers such as Arg1, iNOS, IDO1 in anti-Act1 macrophages. Among activating pathways, we reveal that anti-Act1 macrophage orchestrates NF-kB and STAT3 signaling pathways to upregulate CXCL9/10 secretion and PD-L1 expression. These findings demonstrate that anti-Act1 in macrophage induced a significant shift in MC38 cells gene expression, and modulating the macrophage-cancer is a viable strategy to assist PD-L1 immunotherapy.

2022-09-01 | GSE183971 | GEO

Mapping the anti-cancer activity of α-connexin carboxyl-terminal (aCT1) peptide in resistant HER2+ breast cancer

Project description: This study aims to examine the mechanisms for the anti-cancer effects of a therapeutic peptide agent targeted to connexin 43 (Cx43) called alpha-connexin carboxyl-terminal peptide (aCT1). Findings from this study identify the effect of aCT1 on breast cancer signaling using a resistant HER2+ breast cancer cell line.

2023-12-20 | GSE250543 | GEO

Identification and Characterization of the Mammalian Nuclear RNA N6-Adenosine Methyltransferase Core Complex

Project description:N6-methyladenosine (m6A) is the most prevalent internal modification found in mammalian messenger and non-coding RNAs. The discoveries of functionally significant demethylases that reverse this methylation as well as the recently revealed m6A distributions in mammalian transcriptomes strongly indicate regulatory functions of this modification. Here we report the identification and characterization of the mammalian nuclear RNA N6-adenosine methyltransferase core (RNMTC) complex. Besides METTL3, a methyltransferase which was the only known component of RNMTC in the past, we discovered that a previously uncharacterized methyltransferase, METTL14, exhibits a N6-adenosine methyltransferase activity higher than METTL3. Together with WTAP, the third component that dramatically affects the cellular m6A level, these three proteins form the core complex that orchestrates m6A deposition on mammalian nuclear RNA. Biochemistry assays, imaging experiments, as well as transcriptome-wide analyses of the binding sites and their effects on m6A methylation support methylation function and reveal new insights of RNMTC. PAR-CLIP and m6A-seq in HeLa cells

2013-11-29 | E-GEOD-46705 | biostudies-arrayexpress

IMM_Cleveland LiXX_EAE-Th1 or Th17_Act1 ko mouse_CNS_exp1

Project description:The goal of these studies is to define the molecular signatures of TH1-induced EAE and TH17-induced EAE through adoptive transfer. We will also define the role of IL-17 signaling in the pathology by comparing cells derived from wild type mice to those derived from mice lacking Act1, a key adaptor required for IL-17 dependent signaling. Brains and spinal cords from animals at peak of disease will be profiled.

2017-03-28 | GSE97035 | GEO

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