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Cellular spermine controls autoinflammation by targeting JAK1 to restrain cytokine response

ABSTRACT: Cellular spermine controls autoinflammation by targeting JAK1 to restrain cytokine response

PROVIDER: PRJNA791295 | ENA |

REPOSITORIES: ENA

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Cellular spermine controls autoinflammation by targeting JAK1 to restrain cytokine response

Project description:Using an unbiased metabolomics approach and a IFN-stimulated response elements (ISRE) reporter screening system, we have identified the cellular metabolite spermine as an endogenous brake restraining IFN-I signaling and autoinflammation. Cellular spermine concentration decrease upon stimulations with IFN-I, IL-2, and IL-6. Spermine suppresses phosphorylation of JAK1 in macrophages responding to IFN-I, T cells responding to IL-2, and fibroblasts responding to IL-6. Mechanistically, spermine binds directly to the N-terminal domains of JAK1, resulting in impaired IFNAR2-JAK1 interaction required for initiating downstream signaling and, subsequently, restrained IFN-I effector response. Moreover, spermine attenuates SLE progression in an SLE murine model and reduces IFN-I signaling in PBMCs from SLE patients.

2024-06-21 | GSE192366 | GEO

Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity

Project description:Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity

| PRJNA905367 | ENA

Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity

Project description:Combining metabolomics analyses with an IFN-stimulated response elements reporter system, we identify spermine as a cellular metabolite brake for JAK1 signaling. Spermine directly binds to FERM and SH2 domains of JAK1 to impair IFNAR2-JAK1 interaction. Spermine suppresses JAK1 phosphorylation triggered by types I and II cytokines, including IFN-I/II, IL-2, and IL-6. Spermine treatment attenuates autoimmune pathogenesis in a SLE murine model and reduces IFN-I signaling in monocytes from SLE patients, which have reduced spermine levels.

2024-06-21 | GSE218731 | GEO

Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Human)

Project description:Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Human)

| PRJNA924822 | ENA

Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Mouse)

Project description:Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Mouse)

| PRJNA923703 | ENA

Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Mouse)

2024-06-21 | GSE222887 | GEO

Cellular spermine targets JAK1 to restrain cytokine-mediated autoimmunity (Human)

Project description:Whole blood samples from SLE patients were collected and PBMCs were isolated using Ficoll-PaqueTM PLUS reagent according to the manufacturer’s protocol. The fresh isolated PBMCs from SLE individuals were treated with DMSO or spermine for 3h, PBMCs from healthy control were used as control, then samples were harvested and lysated with Trizol reagend for RNA-sequencing analysis.

2024-06-21 | GSE223097 | GEO

Autoinflammatory keratinization disease with hepatitis and autism reveals roles for JAK1 kinase hyperactivity in autoinflammation.

Project description:Clinical observations reinforced by analysis of a knock-in mouse model confirm the crucial role of JAK1 in regulating physiological inflammatory processes. The present findings expand the phenotypic spectrum resulted from JAK1 hyperactivation and further underscore how gain-of-function JAK1 mutations contribute to multisystem autoinflammation.

2021-12-22 | GSE163100 | GEO

Selective inhibitors of JAK1 targeting a subtype-restricted allosteric cysteine

Project description:The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.

2023-07-20 | PXD031384 | Pride

Transcription profiling of human JAK1 wild-type and JAK1 mutation-positive T cell acute lymphoblastic leukemia blasts

Project description:Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. Somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis; We used microarray to compare the gene expression profile of JAK1 mutation positive or negative ALL blasts Experiment Overall Design: Thawed or freshly isolated T-ALL cells (>90% blasts) were homogenized, total RNA was extracted and hybridized on Affymetrix microarrays

2009-10-02 | E-GEOD-18239 | biostudies-arrayexpress

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