Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA690821 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13389436_1.fastq.gz | Fastqsanger.gz | |||
| SRR13389436_2.fastq.gz | Fastqsanger.gz | |||
| SRR13389437_1.fastq.gz | Fastqsanger.gz | |||
| SRR13389437_2.fastq.gz | Fastqsanger.gz | |||
| SRR13389438_1.fastq.gz | Fastqsanger.gz |
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Project description:Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modeling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorgylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.
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Project description:High levels of inflammation are often present in autoimmune diseases and can impact the functioning of the immune system. Specifically, how surrounding inflammation affects cytokine responses has not been extensively studied. We use IL-6 and IL-27, two cytokines playing opposite roles in inflammation, to ask how cytokines adapt to the inflammatory environment. We show that IL-27 induces a more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identify STAT1 (or STAT3) binding dynamics to GP130 (or IL-27R) as the main parameter contributing to sustained pSTAT1 by IL-27. Mutation of Tyr613 on IL-27R decreased IL-27-induced STAT1 phosphorylation by 80%, with limited effect on STAT3 phosphorylation. The strong receptor/STAT coupling by IL-27 led to the induction of a unique gene expression program by this cytokine, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in Crohn’s disease and SLE patients. IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which can be explained by the higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib lowered the levels of STAT1 activation by IL-6, representing a new strategy to treat auto-immune disorders where cytokine responses are dysregulated.
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Project description:In this study, we compared the effects of two cytokine treatments on the proteome of human Th-1 cells. We used saturating doses of murine single-chain IL-27 (EBI3+p28, 10nM) and HyperIL-6 (20nM) and continuously stimulated cells of three donors with the two cytokines for 24h or left untreated.
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Project description:The allosteric mechanisms that control the different functional and conformational states of oncogenic kinases, and how these molecular switches can be targeted and therapeutically exploited remains largely unexplored. Here we show that c-terminal Tyr 530 is a de facto c- Src auto-phosphorylation site with slow time-resolution kinetics and strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes fast kinetics and a cis-to-trans phosphorylation-switch that controls c-terminal Tyr 530 phosphorylation, enzyme specificity and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of c-terminal Tyr 530 intermolecular phosphorylation between the enzyme and susbtrate acting kinases, and identify a functionally relevant c-terminal palindromic phospho-motif flanking Tyr 530 making important contacts at the interface. Perturbation of this phospho-motif accounts for c-Src disfunction in cancer, as indicated by viral and a colorectal cancer (CRC) associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 auto-phosphorylation and overall phospho-tyrosine activity. However, c-terminal truncated forms display a minor delay in the capacity to phosphorylate intact c-Src substrates surrogates. On the contrary, when these c-terminal variants were used as intact substrate surrogates themselves, they were equally and efficiently phosphorylated, but strikingly they resulted in the allosteric inhibition of the active kinase. Our work reveals a bi-directional crosstalk between activation and c-terminal segments driven by auto-phosphorylation that controls the allosteric interplay between enzyme and susbtrate acting kinases. These findings have important implications for the drug-design and development of next generation c-Src inhibitors targeting non-catalytic and/or allosteric vulnerabilities.
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Project description:Scope: As a result of population ageing, the number of Alzheimer’s disease (AD) patients has rapidly increased. There are many hypothesises on the pathogenesis of AD, but its detailed molecular mechanism is still unknown, and so no effective preventive or therapeutic measures have been established. Some reports showed a decrease in levels of norepinephrine (NE) has been suspected to be involved in the decline of cognitive function in AD patients and NE concentrations were decreased in postmortem AD patient brains. Tyr-Trp was identified as being the most effective dipeptide in enhancing norepinephrine (NE) synthesis and metabolism. And Tyr-Trp treatment ameliorated the short-term memory dysfunction in AD model mice caused by amyloid beta (Aβ) 25-35. So, the purpose of this study was to investigate the preventive or/and protective effects of Tyr-Trp administration in AD model mice. Methods and results: ddY mice were fed normal diet. After 7 days of feeding, mice were divided into 3 groups (n=10 per group) as follows: the sham group, which received saline administration and distilled water injection; the Aβ group, which received saline administration and Aβ peptides 25–35 injection; and the Aβ+YW group, which received Tyr-Trp administration and Aβ peptides 25–35 injection. Tyr-Trp was orally administered Tyr-Trp (100 mg kg-1 day-1, twice a day), starting 7 days before Aβ peptides injection. The other groups received oral administration of saline (5 mL kg-1). After Aβ peptides injection or sham operation, each groups received every oral administration. DAN microarray showed that Tyrosine hydroxylase, dopa decarboxylase and dopamine receptor D2 mRNA expressions which were downregulated in Aβ group comparing with sham group were upregulated in Aβ+YW group comparing with Aβ group. In addition, quinoid dihydropteridine reductase mRNA expression which wasn’t changed in Aβ group comparing with sham group was upregulated in Aβ+YW group comparing with Aβ group. Conclusions: These results suggest that Tyr-Trp administration might ameliorate the short-term memory dysfunction in AD model mice because of enhancing norepinephrine (NE) synthesis and metabolism through metabolism of both Tyr and Trp.
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