TRAIL receptor associates with phosphatase SHP-1 and enables suppressing T-cell receptor signaling via inactivating Lck
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ABSTRACT:
PROVIDER: PRJNA922459 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23033654_1.fastq.gz | Fastqsanger.gz | |||
| SRR23033654_2.fastq.gz | Fastqsanger.gz | |||
| SRR23033655_1.fastq.gz | Fastqsanger.gz | |||
| SRR23033655_2.fastq.gz | Fastqsanger.gz | |||
| SRR23033656_1.fastq.gz | Fastqsanger.gz |
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Project description:We utilized whole-transcriptome RNA sequencing (RNA-seq) in TRAIL-treated activated T cells to identify the gene expression signatures and the possible regulatory pathways associated with TRAIL-R signaling on T-cell activation.
2023-04-06 | GSE222519 | GEO
Project description:BackgroundT cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation.MethodsWhole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells.ResultsTRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation.ConclusionsTRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.
| S-EPMC10967194 | biostudies-literature
Project description:THEMIS is critical for conventional T cell development but its precise molecular function remains elusive. Here we show that THEMIS constitutively associates with the phosphatases SHP-1 and SHP-2. This complex requires the adapter GRB2, which bridges SHP to Themis in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Coherent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knockdown increased TCR-induced TCR- phosphorylation, Erk activation and CD69 expression, however not Lck phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP-1 knockdown. Remarkably, a KI mutation of Lck Ser59, previously suggested to be key in ERK-mediated resistance towards SHP-1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favors T cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T cell development and differentiation.
2015-01-07 | PXD001410 | Pride
Project description:While Lck has been widely recognized to play a pivotal role in the initiation of the T cell receptor (TCR) signaling pathway, an understanding of the precise regulation of Lck in T cells upon TCR activation remains elusive. Investigation of protein-protein interaction (PPI) using proximity labeling techniques such as TurboID has the potential to provide valuable molecular insights into Lck regulatory networks. By expressing Lck-TurboID in Jurkat T cells, we have uncovered a dynamic, short-range Lck protein interaction network upon 30 minutes of TCR stimulation. In this novel application of TurboID, we detected 27 TCR stimulation-induced Lck-proximal interactors in living T cells, including both bona fide and uncanonical Lck interactors, validating the discovery power of this tool. Our results revealed previously unappreciated Lck PPI which may be associated with cytoskeletal rearrangement, ubiquitination of TCR signaling proteins, activation of the MAPK cascade, coalescence of the LAT signalosome, and formation of the immunological synapse. In this study, we demonstrated for the first time in immune cells and for the kinase Lck that TurboID can be utilized to unveil PPI dynamics in living cells at a time scale consistent with TCR signaling.
2020-11-12 | PXD020759 | Pride
Project description:The small heterodimer partner (SHP) regulates fatty acid oxidation and lipogenesis in the liver by regulating peroxisome proliferator-activated receptor (PPAR) γ expression. SHP is also abundantly expressed in the myocardium. Therefore, we investigated the myocardial gene expression in a SHP deletion animal model.
2017-12-01 | E-MTAB-5329 | biostudies-arrayexpress
Project description:Lymphocyte-specific protein tyrosine kinase (Lck) is crucial for signaling from the T cell receptor (TCR) and is controlled through tyrosine phosphorylations. Phosphorylated Tyr505 (pTyr505) promotes a closed, inactive conformation of Lck, while pTyr394 is critical for kinase activity. Additionally, pTyr192 has been suggested to regulate Lck activity by changing the specificity of the Lck Src-homology 2 (SH2) domain and/or by affecting Lck association with CD45 thus drastically increasing pTyr505. However, little is known about how pTyr192 affects endogenously expressed Lck. Here we used CRISPR/Cas9 genome editing to generate Jurkat cell lines expressing Lck Glu192 mimicking Lck pTyr192, or Lck Phe192 mimicking unphosphorylated Lck Tyr192. We confirmed that Lck Glu192 is hyperphosphorylated on Tyr505, possibly explaining reduced association of Lck Glu192 with prototypic Lck-SH2 ligands. To isolate the effect of Lck Tyr192 mutations from the effect on Lck pTyr505, we subsequently generated Jurkat cells doubly mutated on Lck Tyr192 and Lck Tyr505. Both Lck Phe192/Phe505 and Lck Glu192/Phe505 mutants co-precipitated similar amounts of binding partners. Moreover, both mutants displayed hyperphosphorylation of Tyr394. Our results indicate that CD45 is the main phosphatase controlling Lck pTyr394 in steady-state T cells. Additionally, our data demonstrate that the prototypic specificity of the Lck SH2 domain (owned by the Lck Phe192 mutants) promotes transphosphorylation of Tyr394. These observations pinpoint the fundamental role of Tyr192 in regulation of Lck activity and simultaneously reveal the most potent Lck mutants so far described
2021-04-02 | PXD014470 | Pride
Project description:Lysosome-mediated macroautophagy, including lipophagy, is activated under nutrient deprivation but is repressed after feeding. We show that feeding unexpectedly activates intestinal lipophagy in a manner dependent on both the orphan nuclear receptor, small heterodimer partner (SHP/NR0B2), and the late fed-state gut hormone, fibroblast growth factor-15/19 (FGF15/19). Postprandial intestinal triglycerides (TGs) and apolipoprotein-B48 (ApoB48), the TG-rich chylomicron marker, were elevated in SHP-knockout and FGF15-knockout mice. Genomic analyses in mouse intestine revealed that SHP partners with the key lysosomal activator, transcription factor-EB (TFEB), upregulating autophagy/lipolysis network genes after feeding. In HT29 intestinal cells, FGF19 treatment activated lipophagy in a manner dependent on both SHP and TFEB, reducing TG and ApoB48 levels. Mechanistically, feeding-induced FGF15/19 signaling increases nuclear localization of TFEB and SHP via PKCβ/ζ-mediated phosphorylation, leading to transcriptional induction of Ulk1 and Atgl. Collectively, these results demonstrate that after feeding, FGF15/19-activated SHP and TFEB paradoxically activate gut lipophagy, limiting postprandial TG levels. As excess lipids cause dyslipidemia and obesity, the FGF15/19-SHP-TFEB axis that reduces intestinal TGs via lipophagic activation provides promising therapeutic targets for obesity-associated metabolic disease.
2022-04-22 | GSE197549 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress
Project description:Apo2L/TRAIL stimulates cancer-cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyl transferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small cell lung carcinoma and melanoma cell lines (P < 0.00009; n=83), and up to 30% of samples from various human malignancies displayed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-GalNAc-Gal-Sialic acid structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptosis signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a novel link between death receptor O-glycosylation and apoptosis signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy. Keywords: cell type comparison
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