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Identification of TRADD phosphorylation sites

ABSTRACT: We re-introduced Flag-mTRADD into Tradd-/- MEFs, and identified the phosphorylation sites of TRADD which were induced by TNF and inhibited by TAK1 inhibitor 5Z7 using mass spectrometry. We found that TAK1 could mediate the phosphorylation of multiple sites in TRADD upon TNF stimulation. We next performed in vitro kinase assay using recombinant human TAK1 and human TRADD, followed by mass spectrometry to identify the sites directly phosphorylated by TAK1.

ORGANISM(S): Homo Sapiens

SUBMITTER: Junying Yuan

PROVIDER: PXD056588 | iProX | Sat Oct 05 00:00:00 BST 2024

REPOSITORIES: iProX

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Cooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.

Sun Ziyu Z Ye Jianyu J Sun Weimin W Jiang Libo L Shan Bing B Zhang Mengmeng M Xu Jingyi J Li Wanjin W Liu Jianping J Jing Hongyang H Zhang Tian T Hou Meiling M Xie Cen C Wu Rongling R Pan Heling H Yuan Junying J

Nature communications 20250222 1

Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to R ...[more]

PMID: 39987261

Similar Datasets

Cooperation of TRADD- and RIPK1-dependent Cell Death Pathways in Maintaining Intestinal Homeostasis

Project description:Dysfunctional NF-kB signaling is critically involved in Inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-kB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death mediated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and TRADD-dependent colitis. These findings reveal the cooperation between RIPK1 and TRADD in mediating cell death and inflammation in IBD with NF-kB deficiency and suggest the possibility of combined RIPK1 kinase inhibition and TRADD knockout as a new therapeutic strategy for IBD.

2025-01-22 | GSE279034 | GEO

Cooperation of TRADD- and RIPK1-dependent Cell Death Pathways in Maintaining Intestinal Homeostasis [7 DPI colon]

2025-01-22 | GSE279702 | GEO

Cooperation of TRADD- and RIPK1-dependent Cell Death Pathways in Maintaining Intestinal Homeostasis [3 DPI colon]

2025-01-22 | GSE279700 | GEO

ULK1 regulated phosphosites in mouse and human cells

Project description:(1)In vivo SILAC analyses of mouse embryonic fibroblasts (MEFs, triple labeling) were performed comparing phosphorylation events. ULK1 double knock out MEFs (VC) were compared to double knock out MEFs expressing human ULK1 (RE) in fed (DMEM) and starvation (HBSS) conditions. (2) In vivo SILAC analyses of A549 cells (triple labeling) were performed comparing phosphorylation events (195 raw files labeled ""A549""). A549 cells in fed conditions (DMEM) were compared to starved cells (HBSS) and cells treated with rapamycin (Rapa).

2021-11-03 | PXD022303 | Pride

Identification of genes regulated by the phosphotylation of PPARgamma

Project description:In order to identify the molecular mechanisms of PPARgamma phosphorylation at Set273, we generated cell-lines of PPARgamma KO MEFs expressing wtPPARgamma or S273APPARgamma. In addition, because our data showed that PPARgamma ligand drugs such as rosiglitazone and MRL24 blocked this phopshorylation, we treated cells with these drugs, then prepared RNA samples to look at the gene profiling. PPARgamma KO MEFs were introduced by wtPPARgamma or S273APPARgamma. Cells were differentiated for 6 days. Then, wtPPARgamma-introduced KO MEFs were treated with either 1 uM rosiglitazone or 1uM MRL24 for 24h. Cells were harvested and we purified total RNA samples.

2010-06-08 | E-GEOD-22033 | biostudies-arrayexpress

IKK Promotes Cytokine-Induced and Cancer-Associated AMPK Activity and Attenuates Phenformin-Induced Cell Death in LKB1-Deficient Cells

Project description:The 5' AMP-activated protein kinase (AMPK) is a master energy sensing kinase that is regulated by phosphorylation of Thr172 in its activation loop. Three kinases can phosphorylate AMPK at Thr172: the tumor suppressor LKB1, CAMKK2 and TAK1. While LKB1- and CAMKK2-mediated AMPK Thr172 phosphorylation have been well-characterized, much less is known about TAK1-dependent AMPK phosphorylation. An important target of TAK1 is IκB kinase (IKK) which controls NF-B transcription factor activation. Here, we tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172. IKK was required for phosphorylation of Thr172 in AMPK in response to treatment with IL-1 or TNF- treatment or by TAK1 overexpression. Additionally, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could lead to AMPK activation. We found that IKK directly phosphorylated AMPK at Thr172 independently of LKB1 or energy stress. This finding indicated that while LKB1 activates AMPK as a sensor of energetic stress, IKK activated AMPK in response to extracellular inflammatory signals and through distinct pathways downstream of IKK activation. Accordingly, in LKB1-deficient cells, IKK inhibition caused a reduction in AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers.

2018-07-16 | PXD009897 | Pride

Baseline RNA-sequencing data of 12 glioblastoma stem cell lines sensitive or resistant to TAK1 inhibition

Project description:Poor survival and lack of response to current treatment modalities in adult human glioblastomas is attributed to the persistence of a subpopulation of glioma stem cells (GSCs). To identify novel approaches to therapeutically target GSCs, we performed CRISPR/Cas9 knockout screens in GSCs and identified the kinase TAK1 as an important selective survival factor in 50% of the tested GSCs. In sensitive cells, knockout of TAK1 leads to induction of caspase-dependent apoptosis via the RIPK1/Caspase 8/FADD complex due to constitutive, low-level secretion of tumor necrosis factor alpha (TNF-a) and stimulation of TNF receptor 1. Furthermore, we show that expression of genes involved in immune signaling and a mesenchymal signature predict the sensitivity and response of GSCs to TAK1 inhibition. In summary, we have identified TAK1 as a new therapeutic target for mesenchymal GBM and a potential gene signature for selection of patients benefitting from TAK1 targeted therapy.

2023-07-21 | GSE208697 | GEO

CRISPR/Cas9 dropout screen in two glioblastoma stem cell lines with a domain-focused sgRNA library targeting 1387 human proteins involved in epigenetic regulation.

2023-07-21 | GSE208696 | GEO

Quantitative Phospho-proteomic Analysis of TNFα/NFκB Signaling Reveals a Role for RIPK1 Phosphorylation in Suppressing Necrotic Cell Death

Project description:TNFα is a potent inducer of inflammation due to its ability to promote gene expression, inpart via the NFκB pathway. Moreover, in some contexts, TNFα promotes Caspase-dependent apoptosis or RIPK1/RIPK3/MLKL-dependent necrosis. Engagement of the TNF Receptor Signaling Complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of several downstream components, including TAK1, IKKα/IKKβ, IκBα and NFκB. However, immediate downstream phosphorylation events occurring in response to TNFα signaling are poorly understood at a proteome-wide level. Here we use Tandem mass tagging-based proteomics to quantitatively characterize acute TNFα-mediated alterations in the proteome and phosphoproteome with or without inhibition of the cIAP-dependent survival arm of the pathway with a SMAC mimetic. We identify and quantify over 8,000 phosphorylated peptides, among which are numerous known sites in the TNF-RSC, NFκB, and MAP kinase signaling systems, as well as numerous previously unrecognized phosphorylation events. Functional analysis of S320 phosphorylation in RIPK1 demonstrates a role for this event in suppressing its kinase activity, association with CASPASE-8 and FADD proteins, and subsequent necrotic cell death during inflammatory TNFα stimulation. This study provides a resource for further elucidation of TNFα-dependent signaling pathways.

2017-05-30 | PXD006055 | Pride

IRAK4 kinase activity mediates IRF5 activation via IKKβ and TAK1

Project description:IRAK4 kinase plays a critical role in innate immune responses and inflammation by modulating the TLR/IL-1R signaling pathway, yet the mechanism by which it regulates downstream pathways and transcription factors to induce inflammatory cytokines is unclear. IRAK4 can mediate signaling events by mechanisms both dependent and independent of its kinase activity. Understanding this regulation is important for deciphering the role of IRAK4 and for the development of treatments for inflammatory diseases and cancer. Through transcriptomic and biochemical analyses of primary human monocytes treated with a highly potent and selective inhibitor of IRAK4, we show that IRAK4 kinase activity controls the transcription factor IRF5 which in turn induces inflammatory cytokine and type I interferon transcription in myeloid cells. We also show that IRAK4 kinase activity does not control activation of NF-κB. Following TLR stimulation, translocation of IRF5, but not NF-κB, to the nucleus in human monocytes is abolished by IRAK4 kinase inhibition. In addition, binding of IRF5, but not NF-κB p65, to promoters of inflammatory target genes (TNF-α and IP10) is blocked with an IRAK4 kinase inhibitor. IKKβ, a known activator of IRF5, is phosphorylated in response to TLR mediated signaling, and inhibition of IRAK4 kinase blocks IKKβ phosphorylation. Pharmacological inhibition of IKKβ and TAK1, the upstream kinase of IKKβ, in human monocytes blocks IL-1, IL-6 and TNF-α cytokine production, as well as IRF5 translocation to the nucleus. Taken together, our data suggest a novel mechanism by which IRAK4 kinase activity regulates TAK1 and IKKβ activation, leading to the translocation of IRF5 and induction of inflammatory cytokines in human monocytes.

2017-10-12 | GSE86234 | GEO

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