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Activation of a novel ULK1-MLK3-ERK5 pathway by the IFNg receptor is required for IFNg-inducible antiviral responses

ABSTRACT: Activation of a novel ULK1-MLK3-ERK5 pathway by the IFNg receptor is required for IFNg-inducible antiviral responses

PROVIDER: PRJNA486768 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7721690.fastq.gz	Fastqsanger.gz
	SRR7721700.fastq.gz	Fastqsanger.gz
	SRR7721691.fastq.gz	Fastqsanger.gz
	SRR7721701.fastq.gz	Fastqsanger.gz
	SRR7721692.fastq.gz	Fastqsanger.gz

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Activation of a novel ULK1-MLK3-ERK5 pathway by the IFNg receptor is required for IFNg-inducible antiviral responses

Project description:Although well established that signal transducer and activator of transcription 1 (STAT1) activation is required for an interferon (IFN)-mediated antiviral response, the potential roles of other IFNg-activated cellular pathways in the process are unknown. We provide evidence that Unc-51-like kinase 1 (ULK1) is activated during engagement of the Type II IFN receptor and is required for IFNg-mediated transcription of key interferon stimulated genes involved in anti-viral and innate immune responses.

2018-11-20 | GSE118766 | GEO

IFN-γ-inducible antiviral responses require ULK1-mediated activation of MLK3 and ERK5.

Project description:It is well established that activation of the transcription factor signal transducer and activator of transcription 1 (STAT1) is required for the interferon-γ (IFN-γ)-mediated antiviral response. Here, we found that IFN-γ receptor stimulation also activated Unc-51-like kinase 1 (ULK1), an initiator of Beclin-1-mediated autophagy. Furthermore, the interaction between ULK1 and the mitogen-activated protein kinase kinase kinase MLK3 (mixed lineage kinase 3) was necessary for MLK3 phosphorylation and downstream activation of the kinase ERK5. This autophagy-independent activity of ULK1 promoted the transcription of key antiviral IFN-stimulated genes (ISGs) and was essential for IFN-γ-dependent antiviral effects. These findings define a previously unknown IFN-γ pathway that appears to be a key element of the antiviral response.

| S-EPMC6684240 | biostudies-literature

ULK1 as a novel therapeutic target to enhance immune checkpoint therapies against melanoma

Project description:Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. Interferon-gamma (IFNg) signaling and the expression of IFNg-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNg-inducible immunostimulatory genes are required for response to ICIs, chronic IFNg signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of ULK1 correlate with poor survival in melanoma patients and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacological inhibition of ULK1 reduces expression of IFNg-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the PD-L1 promoter region. Additionally, pharmacological inhibition of ULK1 in combination with anti-PD-1 therapy further reduces melanoma tumor growth and enhances anti-tumor immune responses in vivo. Our data suggest that targeting ULK1 represses IFNg-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of melanoma patients to improve response rates and patient outcomes.

2023-02-02 | PXD035347 | Pride

Central Role of ULK1 in Type I Interferon Signaling

Project description:We provide evidence that the Unc-51-like kinase 1 (ULK1) is phosphorylated and activated during engagement of the Type I IFN receptor. Our studies demonstrate that the function of ULK1 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses. Total RNA was isolated from untreated and IFNβ-treated Ulk1/2+/+ and Ulk1/2-/- mouse embryonic fibroblasts (MEFs). Cells were treated for 6 hours with or without mouse IFNβ (2500 IU/ml).

2014-08-26 | E-GEOD-60778 | biostudies-arrayexpress

IFN-inducible phospholipid levels govern endosomal antiviral immunity

Project description:Untargeted lipidomics of 3 cell lines at baseline with focus on phospholipids to understand the role of these lipids in endosomal antiviral immunity

2022-12-16 | ST002413 | MetabolomicsWorkbench

Central Role of ULK1 in Type I Interferon Signaling

2014-08-26 | GSE60778 | GEO

Fumarate hydratase orchestrates hepatic steatosis via ULK1 mediated lipophagy

Project description:Hepatic lipid homeostasis is coordinated by various metabolic pathways, such as lipogenesis, lipid uptake, storage, and oxidation. However, the underlying mechanism that orchestrates metabolic crosstalk remains unclarified. Herein, we demonstrated that fumarate hydratase (FH) functioned as an indispensable adaptor governing mitochondria metabolism and lipid droplets (LDs) degradation. Hepatic FH overexpression prevented hepatic steatosis in normal mice and ob/ob mice without interfering mitochondrial lipid oxidation and lipogenesis. Strikingly, we found that FH selectively activated lipophagy-mediated LDs lipidolysis. Mechanistically, FH interacted with ULK1 and stabilized ULK1 through preventing its ubiquitination and degradation, resulting in lipophagy activation and the elimination of hepatic lipid accumulation. Meanwhile, hepatic ULK1 deficiency abrogated the protective effects in FH-overexpressing mice. Also, we clarified that the interaction between FH and ULK1 occurred in cytoplasm, but not in mitochondria. Cytoplasmic FH was sensitive to lipids and downregulated without affecting mitochondrial FH in vivo. Moreover, the FH-ULK1 axis was identified closely associated with hepatic steatosis in human patients. Taken together, our research demonstrates a “two-side” insight of FH on hepatic lipid metabolism and provides a promising strategy for fatty liver treatment.

2024-02-26 | GSE256510 | GEO

ERK5 Regulates Muscle Cell Fusion through Klf Transcription Factors

Project description:In skeletal muscle differentiation, muscle-specific genes are regulated by two groups of transcription factors, the MyoD and MEF2 families, which work together to drive the differentiation process. Here we show that ERK5 regulates muscle cell fusion through Klf transcription factors. The inhibition of ERK5 activity suppresses muscle cell fusion with minimal effects on the expression of MyoD, MEF2, and their target genes. Promoter analysis coupled to microarray assay reveals that Klf-binding motifs are highly enriched in the promoter regions of ERK5-dependent upregulated genes. Remarkably, Klf2 and Klf4 expression are also upregulated during differentiation in an ERK5-dependent manner, and knockdown of Klf2 or Klf4 specifically suppresses muscle cell fusion. Moreover, we show that the Sp1 transcription factor links ERK5 to Klf2/4, and that nephronectin, a Klf transcriptional target, is involved in muscle cell fusion. Therefore, an ERK5/Sp1/Klf module plays a key role in the fusion process during skeletal muscle differentiation.

2011-02-21 | GSE25827 | GEO

Expression data from Ulk1 silencing in mouse liver and AML12 cells

Project description:This experiments detail the differential gene expressionin hepatic cells in response to Ulk1 silencing both in vivo and in vitro We used microarrays to detail the global programme of gene expression underlying the loss of ULK1 knockdownin hepatic cells

2020-03-27 | GSE147579 | GEO

IFNg+ vs IFNg- Treg

Project description:Gene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood Ex vivo sorted Tregs (CD25highCD127neg) were stimulated for 4 hours and IFNg-secreting cells were detected by a IFNg-capture kit. The samples were resorted based on IFNg expression.

2016-07-01 | E-GEOD-71274 | biostudies-arrayexpress

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