Activation of a novel ULK1-MLK3-ERK5 pathway by the IFNg receptor is required for IFNg-inducible antiviral responses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA486768 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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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
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.
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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
Project description:Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal (GI) malignancies and a major cause of death worldwide, with limited therapeutic options. Although Mixed Lineage Kinase 3 (MLK3), a MAPKKK, has emerged as a key regulator of acute liver injury, inflammation, and non-alcoholic steatohepatitis (NASH), its role in HCC remains unclear. TCGA databases suggest an elevated expression of MAP3K11 (gene of MLK3) and TMA studies show higher MLK3 activation in human HCCs compared to the normal livers. We demonstrate here that MLK3 kinase activity is upregulated in Diethylnitrosamine/phenobarbital (DEN/PB)-induced HCC, and MLK3 deficiency (MLK3-/-) alleviates HCC progression. Histological and biochemical analyses reveal that MLK3-/- reduces DEN/PB induced cell proliferation in vivo and MLK3 inhibition by si/shRNA or pharmacological inhibitors reduces cell proliferation and colony formation in vitro. Interestingly, MLK3-/- does not impair DEN-induced liver injury phenotypes at the early stage. RNA-sequencing analysis shows that MLK3-/- modulates the gene signature of various biological pathways, including epithelial-mesenchymal transition (EMT), and reduces TGFβ1&2 expressions. HCC cells overexpressing MLK3 promote EMT, and induction of TGFβ, suggesting MLK3 to be an upstream regulator of TGFβ signaling. In addition, MLK3-/- significantly reduces the activated hepatic stellate cell (HSC) signature, which is increased in DEN/PB-Wild-Type livers. Further analysis suggested that MLK3 might promote a paracrine increase in TGFβ expression leading to pSmad2 induction and HSC activation. Our work thus shows that MLK3 promotes HCC proliferation, TGFβ expression, and HSC activation, implying that pharmacological inhibition of MLK3 may have a significant clinical impact on HCC progression.
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Project description:Mixed Lineage Kinase 3 (MLK3) is a viable emerging target for neoplastic diseases; however, it is uncertain whether its activators or inhibitors can act as anti-neoplastic agents. Previously, we reported that the kinase activity of MLK3 was significantly higher in triple-negative breast cancer (TNBC) than hormone receptor-positive human breast tumors where estrogen inhibits MLK3 kinase activity and provides a survival advantage to ER+ breast cancer cells. Here, we identified that in TNBC, the higher MLK3 kinase activity paradoxically promotes cell survival via activating the downstream PAK1-NF-kB axis. The MLKs/MLK3 inhibitors, CEP-1347, and URMC-099 induced cell death in TNBC but not in hormone receptor-positive breast cancer cells. The MLKs/MLK3 inhibitors reduced TNBC cell line and patient-derived xenografts’ tumor burden. The MLKs/MLK3 inhibitors also decreased MLK3, PAK1, and NF-kB protein expression and activation, prompting cell death in breast PDXs. The RNA-seq analyses indicated several genes downregulated upon MLKs/MLK3 inhibition in tumors. Significantly NGF/TrkA MAPK pathway was enriched in tumors undergoing tumor reduction by CEP-1347 and URMC-099. The tumors or cell lines that did respond to MLKs/MLK3 inhibitors had higher TrkA expression, and TrkA overexpression in the presence of MLK3 sensitized the TNBC cell line that initially did not respond to MLKs/MLK3 inhibitors. These results suggest that the functions of MLK3 in cancer cells are dependent on downstream targets/signaling, and rationalized decision needs to be made before using its inhibitor in different breast cancer subtypes. Our data also highlight that MLK3 inhibitor warrants further investigation for treating TNBC.
2023-03-01 | GSE188947 | GEO
Project description:MLK2 and MLK3 are key regulators of angiogenesis, particularly under hypoxic conditions. To investigate the underlying mechanisms, we performed unbiased RNA sequencing on primary lung endothelial cells isolated from wild-type and MLK2 and MLK3 double knockout (MLK2-/-MLK3-/-) mice exposed to normoxia or hypoxia. Transcriptomic analysis revealed significant enrichment of the “Pathways in cancer” and “HIF1α signaling pathway,” which regulate proangiogenic genes. Our RNA Seq data suggest that, mechanistically, MLKs act through the long noncoding RNA H19 to regulate angiogenic gene expression. These findings identify the MLK-H19 axis as a critical regulator of endothelial function and a key driver of tumor-associated angiogenesis
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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
Project description:MLK3 gene mutations were described to occur in about 20% of microsatellite unstable gastrointestinal cancers and to harbor oncogenic activity. In particular, mutation P252H, located in the kinase domain, was found to have a strong transforming potential, and to promote the growth of highly invasive tumors when subcutaneously injected in nude mice. Nevertheless, the molecular mechanism underlying the oncogenic activity of P252H mutant remained elusive.In this work, we performed Illumina Whole Genome arrays on three biological replicas of human HEK293 cells stably transfected with the wild-type MLK3, the P252H mutation and with the empty vector (Mock) in order to identify the putative signaling pathways associated with P252H Our results showed that mutant MLK3 exerts its oncogenic effects by deregulating several important colorectal cancer- associated signaling pathways such as WNT, MAPK, NOTCH, TGF-M-NM-2 and P53. A more detailed analysis of the alterations affecting the WNT signaling pathway revealed a down-regulation of molecules involved in the canonical pathway, such as DVL2, LEF1, CCND1 and c-Myc, and an up- regulation of DKK, a well-known negative regulator of canonical WNT signaling, in MLK3 mutant cells. Additionally, FZD6 and FZD10 genes, known to act as negative regulators of the canonical WNT signaling cascade and as positive regulators of the planar cell polarity (PCP) pathway, a non-canonic WNT pathway, were found to be up-regulated in P252H cells. 9 samples, 2 conditions with 3 biological replicates per condition
2014-03-21 | E-GEOD-54611 | biostudies-arrayexpress
Project description:MLK3 gene mutations were described to occur in about 20% of microsatellite unstable gastrointestinal cancers and to harbor oncogenic activity. In particular, mutation P252H, located in the kinase domain, was found to have a strong transforming potential, and to promote the growth of highly invasive tumors when subcutaneously injected in nude mice. Nevertheless, the molecular mechanism underlying the oncogenic activity of P252H mutant remained elusive.In this work, we performed Illumina Whole Genome arrays on three biological replicas of human HEK293 cells stably transfected with the wild-type MLK3, the P252H mutation and with the empty vector (Mock) in order to identify the putative signaling pathways associated with P252H Our results showed that mutant MLK3 exerts its oncogenic effects by deregulating several important colorectal cancer- associated signaling pathways such as WNT, MAPK, NOTCH, TGF-β and P53. A more detailed analysis of the alterations affecting the WNT signaling pathway revealed a down-regulation of molecules involved in the canonical pathway, such as DVL2, LEF1, CCND1 and c-Myc, and an up- regulation of DKK, a well-known negative regulator of canonical WNT signaling, in MLK3 mutant cells. Additionally, FZD6 and FZD10 genes, known to act as negative regulators of the canonical WNT signaling cascade and as positive regulators of the planar cell polarity (PCP) pathway, a non-canonic WNT pathway, were found to be up-regulated in P252H cells.
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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.
2014-08-26 | GSE60778 | GEO